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Dissecting Histone Deacetylase 3 in Multiple Disease Conditions: Selective Inhibition as a Promising Therapeutic Strategy

Cite this: J. Med. Chem. 2021, 64, 13, 8827–8869
Publication Date (Web):June 23, 2021
https://doi.org/10.1021/acs.jmedchem.0c01676
Copyright © 2021 American Chemical Society
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Abstract

The acetylation of histone and non-histone proteins has been implicated in several disease states. Modulation of such epigenetic modifications has therefore made histone deacetylases (HDACs) important drug targets. HDAC3, among various class I HDACs, has been signified as a potentially validated target in multiple diseases, namely, cancer, neurodegenerative diseases, diabetes, obesity, cardiovascular disorders, autoimmune diseases, inflammatory diseases, parasitic infections, and HIV. However, only a handful of HDAC3-selective inhibitors have been reported in spite of continuous efforts in design and development of HDAC3-selective inhibitors. In this Perspective, the roles of HDAC3 in various diseases as well as numerous potent and HDAC3-selective inhibitors have been discussed in detail. It will surely open up a new vista in the discovery of newer, more effective, and more selective HDAC3 inhibitors.

1. Introduction

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1.1. HDAC and Epigenetic Modulations

Epigenetic manipulations, referred to as alterations of genetic expression, are associated with chemical modulations of cytosine residues of DNA as well as histone proteins.(1−3) Epigenetic modifications through alterations by both histone deacetylases (HDACs) and histone acetyltransferases (HATs) regulate numerous genetic expressions.(4,5) HDACs catalyze the deletion of an acetyl group from the acetylated ε-amino lysines of histone proteins (Figure 1).

Figure 1

Figure 1. Lysine deacetylation of histone proteins catalyzed by HDAC.

Subsequently, HDACs are involved in transcription processes as well as chromatin condensation mechanisms.(6) Nevertheless, HDACs modulate numerous signaling pathways and control normal and diseased pathophysiological conditions.(7,8) Therefore, the overexpression of HDACs has been found to alter normal epigenetic mechanisms and to correlate with numerous disease conditions.

1.2. Classification of HDACs

In mammals, based on the phylogenetic analysis of protein sequences, HDACs have been categorized into four different classes, class I, II, III, and IV(9) (Figure 2, Table 1).

Figure 2

Figure 2. Different classes of HDACs.

Table 1. Detailed Classification of HDAC Family Members
HDAC      
classmembersequence homologychromosomal locationexpression in tissuescatalytic domain (amino acid sequences)complexsubstratea
IHDAC1yeast RDP3 deacetylase1p34ubiquitous9–321Sin3, NuRD, CORESThistones (H2), p53 (TP53), E2F-1, STAT3 (STAT3), GATA (GATA), AR (AR), pRB (Rb1), MeCP2 (MECP2), MyoD (MYOD), ATM (ATM), DNMT1 (DNMT1), SHP (NR0B2), NF-κB (NFKB1), MEF2 (MEF2)
HDAC2yeast RDP3 deacetylase6q21ubiquitous9–322Sin3, NuRD, CORESThistones (H2), HOP (HOP), GATA2 (GATA2), Bcl-6 (BCL6), STAT3 (STAT3), glucocorticoid receptor (NR3C1), NF-κB (NFKB1), pRb (Rb1), BRCA1 (BRCA1)
HDAC3yeast RDP3 deacetylase5q31ubiquitous3–316NCOR/SMRT, NCOR1/NCOR2, GPS2-TBL1XSTAT3 (STAT3), GATA1 (GATA1), RelA (Rela), YY-1 (YY1), MEF2D (MEF2D), SHP (NR0B2), histones (H2), pRb (Rb1), NF-κB (NFKB1)
HDAC8yeast RDP3 deacetylaseXq13ubiquitous14–324EST1BSMC3 (SMC3), HSP70 (HSP70)
IIaHDAC4yeast HDA1 deacetylaseq37.2smooth muscle, heart, brain655–1084NCOR1/NCOR2, ANKRA, RFXANRhistones (H2), GATA1 (GATA1), GCMa (GCM1), p53 (TP53), SRF (SRF), p21, Runx2 (RUNX2), HP1 (HP1α), HIF-1α (HIF1A), FOXO (FOXO), SUV39H1 (SUV39H1)
HDAC5yeast HDA1 deacetylase17q21smooth muscle, heart, brain684–1028REA, estrogen receptorSmad7 (SMAD7), GCMa (GCM1), HP1 (HP1α), MEF2 (MEF2), YY1 (YY1), CaM (CAM), Runx2 (RUNX2)
HDAC7yeast HDA1 deacetylase12q13.1smooth muscle, pancreas placenta, heart518–865Sin3, NCOR2, Bcl-6, HIF-1αFLAG1 (flaG1), FLAG2
HDAC9yeast HDA1 deacetylasep21-p15kidney, liver, pancreas, heart631–978FOX3Phistones (H2), Runx2 (RUNX2), CaM (CAM), HIF-1α (HIF1A), PML (PML), MEF2 (Mef2)
IIbHDAC6 Xp11.22-23 87–404, 482–800RUNX2Smad7 (SMAD7), SHP (NR0B2), α-tubulin (TUBA1A), HSP90 (HSP90), Runx2 (RUNX2), cortactin (CTTN)
HDAC10 22q13.31 1–323NCOR2PP1 (PP1), HSP90 (HSP90), LcoR (LCOR)
IVHDAC11class I and II HDACs3p25.2 14–326 histones (H2), Cdt1 (CDT1)
a

The names of the respective genes of these substrate proteins are shown in parentheses.

Class I HDACs (namely, HDAC1, HDAC2, HDAC3, and HDAC8) are expressed in the nucleus and are related to the reduced potassium dependency 3 (Rpd3) gene found in yeast even though HDAC3 shuttles between the nucleus and cytoplasm.(10,11) Class I HDACs are composed of a distinctive deacetylase domain. The HDACs belonging to class II are found in both the nucleus and cytoplasm. They are again grouped in two classes, class IIA and class IIB. These class II HDACs display a structural resemblance to the yeast gene Hda1.(12) HDAC4, HDAC5, HDAC7, and HDAC9 are combined in class IIA. However, two other HDACs, HDAC6 and HDAC10, are combined in class IIB. Along with the deacetylase domain, class IIA HDACs possess an N-terminal domain that includes a distinct myocyte enhancer factor (MEF) binding region.(9,13) However, class IIB HDACs possess a unique C-terminal domain. HDAC6, a class IIB enzyme, possesses a zinc-finger ubiquitin binding domain (ZnF-UBP), whereas HDAC10 contains a leucine-rich domain.(9) The distinct HDAC6 N-terminal domain helps to deacetylate α-tubulin.(14) The class IV HDAC, HDAC11, enzyme is found in both nucleus and cytoplasm.(15) Interestingly, sirtuins (SIRT1–SIRT7) are categorized as class III HDACs. However, their functions are not associated with class I and class II HDACs. Both the class I and class II HDACs are completely Zn2+-ion-dependent, whereas the sirtuins (SIRT1–SIRT7) are NAD+-dependent. Each HDAC displays a high degree of structural homology at the active site because of the presence of a conserved tyrosine residue that takes part in the catalytic mechanism. In mammals, class IIA HDACs possess a histidine instead of the tyrosine residue, which reduces the catalytic activity.(9,13)

1.3. HDAC Inhibitors Modulate Diverse Biological Processes

Due to the activity of HDACs in histone deacetylation and epigenetic modulations, HDACs participate in numerous biological signaling events.(6,7) Apart from maintaining a variety of normal physiological events, HDACs modulate several pathophysiological and disease conditions, namely, cancers, neurodegenerative disorders, inflammatory diseases, metabolic disorders, autoimmune diseases, etc.(5−7) HDAC inhibitors are found to modulate a variety of diverse biological activities and cellular functions, as well as various genetic manipulations related to tumor growth inhibition, apoptosis, cell cycle arrest, cell migration and motility, autophagy, antiangiogenic effects, DNA repair, and mediation of nuclear and inflammatory signaling processes(16−18) (Figure 3, Table 2).

Figure 3

Figure 3. HDAC inhibitors in modulating diverse biological conditions.

Table 2. HDAC Inhibitors Modulating Diverse Biological Processes
functionrole of HDAC inhibitors
cell cycle arrest(a) induction of endogenous CDK inhibitor p21;(19−21) (b) induction of p27 related to CDK inhibitory activity;(17) (c) downregulation of cyclin D and cyclin A genes to decrease CDK activities;(17,22) (d) downregulation of c-myc expression;(23) (e) disruption mitotic spindle assembly and checkpoints(24−26)
DNA synthesisdownregulation of thymidylate synthetase and CTP synthase(17)
cell migration and motility(a) upregulation of RECK protein which further downregulates MMP-2, MMP-9 and MMP-14;(17,27) (b) upregulation of TIMP-1 and TIMP-3;(17,28) (c) hyperacetylation of tubulin and subsequent decrease in microtubule dynamics;(29)
apoptosis(a) upregulation of pro-apoptotic proteins (namely, Bid, Bim, Bmf, and Noxa) via p53 acetylation;(30−34) (b) induction of genes related to mitochondrial damage (such as apaf1, cytC, and casp9);(17,35) (c) downregulation of antiapoptotic proteins (namely, Bcl2, BCL-XL, c-FLIP, MCL-1, survivin, and XIAP);(36−39) (d) upregulation of TRAIL, Fas, Fas-L and TNF-α-guided activation of caspases;(17,38−40) (e) downregulation of FLIP and IAP2(38−41)
DNA damage(a) induction of the accumulation of ROS followed by induction of mitochondrial disruption and DNA damage;(42−45) (b) downregulation of the expression of genes for DNA repair proteins, namely, BRCA1, BRCA2, RAD51, and Ku70;(46−50) (c) downregulation of TrX but upregulation of TBP2(51)
antiangiogenesisrepression of pro-angiogenic proteins like VEGF, HIF-1α, and CXCR4(17,52−55)
immunomodulation(a) upregulation of the MHC class I and class II proteins and ICAM1;(56,57) (b) reduction of the secretion of pro-inflammatory cytokines, namely, TNFα, IL-1, and IFNγ(58,59)
autophagyinduction of caspase-independent autophagic cell death(17,60)
other diverse biological activities(a) hyperacetylation of several transcription factors and proteins, namely, p53,(61) NF-κB,(62) and α-tubulin;(63) (b) inactivation of STAT1,(64) STAT3,(65) and STAT5;(66,67) (c) activation of JNK;(68,69) (d) hyperacetylation of chaperone proteins, such as HSP90;(70,71) (e) reduction of proteasome function;(72,73) (f) disruption of aggresome to degrade misfolded proteins(17,74,75)
a

CDK, cyclin-dependent kinase; RECK, reversion-inducing cysteine-rich protein with Kazal motifs; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of matrix metalloproteinase; c-FLIP, cellular FLICK-like inhibitory protein; MCL-1, myeloid cell leukemia sequence-1; XIAP, X-linked inhibitor of apoptosis; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; TNF-α, tumor necrosis factor-α; FLIP, Flice inhibitory protein; IAP2, inhibitor of apoptosis 2; ROS, reactive oxygen species; Trx, thioredoxin; TBP2, TrX-binding protein; VEGF, vascular endothelial growth factor; HIF-1α, hypoxia inducible factor-1α; CXCR4, C-X-C chemokine receptor type 4; MHC, major histocompatibility complex; ICAM1, intracellular adhesion molecule-1; IL-1; interleukin-1; IFNγ, interferon-γ; STAT, signal transducer and activator of transcription; JNK, Janus kinase; HSP90, heat shock protein 90.

Depending on the diverse biological activities of HDACs, various HDAC inhibitors have been synthesized. A few of these inhibitors have been marketed for treating particular cancers. However, most of them have been evaluated in various phases of clinical trials(1,5,6,8) (Figure 4). The HDAC inhibitory profile of these compounds is listed in Table 3.

Figure 4

Figure 4. Approved and clinically evaluated HDAC inhibitors.(76−107)

Table 3. Inhibitory Profile of the Approved and Clinical Phase HDAC Inhibitors
 HDAC isoform IC50 (nM)
drug1238457961011
vorinostat (1)(108)75.536257.41069150561631252278.127.188.4109
belinostat (2)(108)17.633.321.1157123676.359844.214.531.344.2
panobinostat (3)(108)2.513.22.12772037.85315.710.52.32.7
trichostatin (4)(109)5810200500026001400104000.74010
abexinostat (5)(110)21631483706048350168125214
resminostat (6)(111)42.5 50.1877    71.8  
givinostat (7)(110)133293136837>1000532524512312331287
pracinostat (8)(112)49964314056471377010084093
bisthianostat (9)(110)413617>1000>1000>1000>10002278
quisinostat (10)(110)0.10.3540.6411932770.50.4
ricolinostat (11)(110)584851100>1000>1000>1000>10005>1000
CUDC-101 (12)(113)4.512.69.179.813.211.437367.25.126.1
tucidinostat (13)(114)9516067733>30000>30000>30000>30000>3000078432
tacedinaline (14)(110)9009001200>10000       
entinostat (15)(114)2623064992700>30000>30000>30000>30000>30000254649
mocetinostat (16)(115)1502901660>10000>10000>10000>10000 >10000 590
domatinostat (17)(116)160370130>15000>15000>15000>15000>15000>15000>15000>15000
romidepsin (18)(110)111>1000647>1000>1000>100022610.3
Due to pan-HDAC inhibition, HDAC inhibitors produce a number of unacceptable adverse effects (such as neutropenia, thrombocytopenia, hypokalemia, elevated creatinine and uric acid, dehydration, anorexia, nausea, vomiting, diarrhea, flushing, fatigue, and atrial fibrillation),(117,118) and therefore, only a few have been approved for limited use to treat specific cancers (Figure 4).(5,6,110) Therefore, it is inferred that isoform-selective HDAC inhibition not only may help to get rid of the off-target adverse effects but also may be effective in combating various disease conditions. In view of the selectivity and specificity, HDAC3 has been established to be a promising and attractive target to combat multiple diseases. In our earlier communication, we briefly mentioned the implication of HDAC3 in several disease conditions, but focused extensively on almost all the existing HDAC3 inhibitors including their description and detail structure–activity relationship (SAR) analysis.(5) However, in this Perspective, the details of implication of HDAC3 in various disease conditions, including the signaling pathways, as well as the development of potent HDAC3-selective inhibitors, have been discussed extensively. Though HDAC3 is a validated target and HDAC3 selectivity is crucial to avoid off-target toxicity, a number of potent HDAC3 inhibitors remain untested against other HDACs. Therefore, the HDAC3 selectivity issue still remains untested due to incomplete HDAC inhibitory profiling of these compounds. Despite evaluating the HDAC3 inhibitory potency only, compounds should be evaluated for their HDAC3 selectivity over other HDACs, so that proper lead molecules may be identified for further modification. This may be the major limitation regarding the selectivity toward HDAC3. In spite of these limitations, this Perspective will be able to provide detailed implications of HDAC3 in various disease conditions and may help to design newer HDAC3-selective inhibitors in order to develop newer therapies against various diseases related to HDAC3.

2. Structure of HDAC3

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All class I HDAC enzymes (namely, HDAC1, -2, -3, and -8) exhibit structural resemblance to the yeast RPD3 protein. HDAC1 and HDAC2 were initially identified in human beings and subsequently cloned.(119,120) Later, the identification of HDAC3 via homology modeling revealed that HDAC3 is encoded in a similar manner to RPD3 proteins but possesses quite a dissimilar structure compared to HDAC1 and HDAC2.(121) Other than different organs, it is highly expressed in various parts of the brain, namely, cerebellum, hippocampus, cortex, hypothalamus, striatum, amygdala, neurons, and astrocytes.(122,123)
HDAC3 has been found to form a stable complex with nuclear receptor co-repressor (N-CoR) as well as silencing mediator of retinoic acid thyroid receptor (SMRT).(5,124−128) HDAC3 catalyzes deacetylation and represses transcriptional mechanisms.(125) HDAC3 along with N-CoR/SMRT modulates the repression of several nuclear receptors, including thyroid hormone receptor (TR), retinoid X receptor (RXR), retinoic acid receptor (RAR), peroxisome proliferator-activated receptor (PPAR), DAX1, Rev-Erb, and COUP-TFs.(124) Apart from the nuclear receptors, several transcription factors also bind to the complex to form the inactive state of target genes.(124) During HDAC3 activation, the deacetylation activating domain (DAD) modulates SMRT activity in the nuclear receptor co-repressor (N-CoR) complex.(5,129) DAD has a pair of SANT motifs (SANT1 and SANT2) located at the N-termini of SMRT and N-CoR. The highly conserved SANT2 region acts as an essential part of the histone interacting domain (HID) that is crucial for both HDAC3 binding and activation.(5,124,127) Again, the nonconserved C-terminal region is crucial for the deacetylation and repression of transcription processes. The central part of HDAC3 contains a nuclear export signal (NES) and the C-terminal end is responsible for the localization of protein in the nucleus. Moreover, the N-terminal portion is responsible for forming oligomers.(130)
Watson et al.(131) found that HDAC3 does not form a complex with SMRT–DAD in bacteria but forms a complex with SMRT–DAD in mammalian HEK293 cells. Compared to other class I HDACs (namely, HDAC8 and HDAC2), HDAC3 possesses eight β-sheets encompassed by α-helices. A unique tyrosine residue (solvent-exposed) is found near the active site tunnel. The tyrosine residue is supposed to interact with the substrate to regulate substrate specificity. During complex formation with HDAC3, the N-terminal helix of DAD evolves a structural reorganization and resides along the HDAC3 surface forming numerous intermolecular interactions. The SMRT–DAD complex is found to interact with the HDAC3 N-terminal region, forming helices H1–H2, loop L2, and strand S2. Interestingly, this region of HDAC3 is quite dissimilar to HDAC8. The H1 helix of HDAC3 is distorted and looks like a pseudohelix. Due to this structural difference, it may be considered that HDAC8 becomes active without interacting with any co-repressor. The d-myo-inositol-1,4,5,6-tetrakisphosphate [Ins(1,4,5,6)P4] links HDAC3 and DAD (Figure 5). Both HDAC3 and SMRT–DAD form hydrogen bonds with amino acids.(131)

Figure 5

Figure 5. (A) Structure of HDAC3 (PDB 4A69) [A chain, indigo; B chain, yellow; C chain, red; D chain, green; zinc ions are shown as magenta spheres; [Ins(1,4,5,6)P4] is located in the interface of A, B and C chains shown as scaled ball and stick model]. (B) Intermolecular interactions of zinc, acetate and surrounding amino acids at A chain. (C) Intermolecular interactions of zinc, acetate, and surrounding amino acids at B chain.

Due to such interactions, Ins(1,4,5,6)P4 is firmly associated with the complex. Ins(1,4,5,6)P4 is a mandatory precondition for the interaction between HDAC3 and SMRT, and it acts like an “intermolecular glue”.(131) Importantly, all the three components, Ins(1,4,5,6)P4, HDAC3, and SMRT–DAD, are necessary for the activation of HDAC3 enzyme. An acetate molecule forms hydrogen bonds to the catalytic Zn2+ ion as well as His134 and Tyr298 (Figure 5).(131) The binding surfaces of both Ins(1,4,5,6)P4 and DAD are situated on the same side of the HDAC3 active site. Conformational changes in Ins(1,4,5,6)P4 and DAD occur during binding to HDAC3. This phenomenon assists in substrate binding and, subsequently, accelerates the enzymatic activity of HDAC3. Compared to HDAC3, the substrate binding mode at the active site of HDAC8 is not dependent on any complex formation. Importantly, in the case of HDAC3, mutations or alterations in Arg265, as well as loop L1 and L6, cause not only the loss of deacetylation but also the abolishment of interactions with SMRT–DAD. Nevertheless, Ins(1,4,5,6)P4 is also a crucial constituent for HDAC3 activity as suggested by the reconstitution assay in vitro.(131)

2.1. Understanding Isoform Selectivity in Terms of Binding Mode of Interactions between HDAC Inhibitors and HDACs

Because different HDAC inhibitors have different binding modes with different HDACs, the pattern of binding orientations may provide newer ideas to design isoform-selective HDAC inhibitors. For example, some potential HDAC inhibitors such as SK-683 (19, Figure 6), CG-1521 (20, Figure 6), and NVP-LAQ824 (21, Figure 6) along with some well-known clinically evaluated HDAC inhibitors, namely, SAHA (1, Figure 4), TSA (4, Figure 4), and MS-275 (15, Figure 4) were considered for their binding interactions with several HDACs by Wang and co-workers.(132)

Figure 6

Figure 6. Potential HDAC inhibitors used to evaluate the binding pattern and orientation with several HDACs

The molecular docking study of HDAC inhibitors, TSA (4), SK-683 (19), and CG-1521 (20), conducted by Wang et al.(132) demonstrated structural variation among different class I HDACs (Figure 7).

Figure 7

Figure 7. Structures of docked TSA (4, green), SK-683 (19, purple), and CG-1521 (20, cyan) in the active sites of HDAC1 (a), HDAC2 (b), HDAC3 (c), and HDAC8 (d) (left) and their top views in these proteins with surface representations (right). Reprinted with permission from ref (132). Copyright 2005 American Chemical Society.

The similar binding pattern of trichostatin A (TSA, 4) into all class I HDACs suggests its nonselective behavior (Figure 7a). The docked conformation of TSA (4) also displays a similar binding orientation as in the X-ray cocrystal structure of HDLP–TSA. The hydroxamate zinc binding group (ZBG) of TSA (4) binds to the catalytic Zn2+ ion at the bottom of the 11 Å channel, whereas the associated long aliphatic chain lies in the 11 Å channel. However, the aromatic cap group is located close to Glu98 (HDAC1), Glu99 (HDAC2), or Asp92 (HDAC3).(132) Again, the binding of SK-683 (19) with HDAC1 is found to be different from the binding with HDAC2 and HDAC3. The orientation of two aromatic groups of SK-683 (19) is slightly shifted for HDAC2 and HDAC3 compared to the respective orientation in HDAC1 (Figure 7b).(132) On the other hand, CG-1521 (20) binds close to the 11 Å channel, but the rigid aromatic portion is oriented differently for all HDACs compared to the binding orientation of SAHA (1) and SK-683 (19) (Figure 7c).(132) Apart from HDAC3, TSA (4) is found to bind more strongly with HDAC1 and HDAC2 compared to the other compounds.
On the other hand, the binding energy suggests that SAHA (1) binds to HDAC1, HDAC3, and HDAC8 in a similar orientation, but it is a weaker inhibitor than TSA (4) (Figure 8a).(132)

Figure 8

Figure 8. Structures of docked SAHA (1, blue), MS-275 (15, red), and NVP-LAQ824 (21, yellow) in the active sites of HDAC1 (a), HDAC3 (b), and HDAC8 (c). Reprinted with permission from ref (132). Copyright 2005 American Chemical Society.

Interestingly, the similar values of binding energies of SAHA (1) with HDAC1, HDAC3, and HDAC8 also reveal it to be a nonselective one. In the case of MS-275 (15), the close binding interaction energies as well as the similar patterns of binding with both HDAC1 and HDAC3 suggest that it is a dual inhibitor of HDAC1/3. Interestingly, the binding of MS-275 (15) with HDAC8 is completely different compared to binding with HDAC1 and HDAC3 (Figure 8b).(132) It does not bind to the active site of HDAC8 but binds into another cavity. This suggests the presence of a second binding site in HDAC8, and MS-275 (15) is a weak inhibitor of HDAC8. Inhibitor NVP-LAQ824 (21) binds more strongly to HDAC3 compared to HDAC1 and HDAC8. The binding orientation with HDAC3 is also completely different compared to the corresponding binding with HDAC1 and HDAC8 (Figure 8c).(132) Due to the minute change at the binding pocket (Glu98 in HDAC1 vs Asp92 in HDAC3), the orientation of the indolyl cap group of NVP-LAQ824 (21) becomes different. This makes the compound bind strongly at the active site of HDAC3.(132) Such structural differences as well as different binding interactions along with spatial orientations might be helpful in designing isoform-selective HDAC3 inhibitors.

3. HDAC3 in Multiple Disease Conditions

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HDAC3 is a vital HDAC from class I that has been found to play crucial roles in a variety of disease conditions (Figure 9).

Figure 9

Figure 9. Role of HDAC3 in various disease conditions.

HDAC3 plays essential roles in modulating several diseases, such as cancers,(133−136) inflammatory disease conditions,(137) metabolic disorders, interstitial fibrosis, autoimmune disorders (such as rheumatoid arthritis),(138) neurodegenerative and CNS disorders [namely, schizophrenia,(139) spinal cord injury,(140,141) learning and memory dysfunction,(3,142) amyotrophic lateral sclerosis (ALS),(143) major depressive disorder (MDD),(144) spinocerebellar ataxia,(122,145) Parkinson’s disease (PD),(146) Huntington’s disease (HD),(122,147,148) and Alzheimer’s disease (AD)(149,150)], cardiovascular diseases and hypertension,(151−153) diabetes,(154−156) parasitic infections (namely, taxoplasmosis)(157,158) and HIV.(159−161) Therefore, designing potential HDAC3 inhibitors should be an essential and intended criterion for accelerating the drug discovery processes against the above-mentioned diseases in the near future.

3.1. HDAC3 in Cancer

Various studies report diverse functions of HDAC3 in different cancers. HDAC3, an epigenetic modulator in DNA damage and repair, maintains chromatin structure and genome stability.(129,162−164) HDAC3 takes part crucially in histone deacetylation, DNA damage, DNA double strand break repair, and apoptosis.(129,162) It is found to be frequently overexpressed in various cancers, including chronic lymphocytic leukemia, gastric and liver cancer, breast cancer, and renal and colon cancers.(5,165) It was noted that downregulation of HDAC3 decreases tumor proliferation.(166,167) HDAC3 also regulates cancer progression through various pathways such as transforming growth factor β (TGFβ), Wnt, and interferon signaling.(167) Moreover, downregulation of HDAC3 helps to upregulate the vitamin D receptor (VDR) gene during cellular arrest in various cancer cells.(167−169) HDAC3 also indirectly modulates the acetylation of tubulin protein as seen in the PC3 cell line.(170) HDAC3 is associated with the transcriptional modulation of numerous cytokines implicated in immune responses related to cancer and inflammation.(171) The pro-IL-16 protein forms a complex with HDAC3, which results in the suppression of Skp2 gene transcription, which in turn leads to the cell cycle arrest.(172) HDAC3 also suppresses the activity of GATA binding protein 2 (GATA2), which has been correlated with non-small-cell lung cancer (NSCLC) governed by Ras protein.(173,174) HDAC3 was also found to deacetylate STAT1 to modulate its phosphorylation as well as nuclear translocation.(175) During mitosis, HDAC3 is complexed with A-kinase anchor protein 95 (AKAP95) and HA95 protein, which are required for histone deacetylation. Again, HDAC3 and AKAP95/HA95 are also important for phosphorylation of histone H3 at Ser10 (i.e., H3S10 phosphorylation). HDAC3 inhibition may therefore cause a decrease in H3S10 phosphorylation along with an increased level in histone acetylation in mitotic cell cycle arrest.(134) Nevertheless, the activity of HDAC3 is divergently mediated through phosphorylation of c-Jun N-terminal kinase (JNK) in triple-negative breast cancer (TNBC).(176) Apart from that, the JNK phosphorylation also increases HDAC3 phosphorylation affecting both inhibitor binding and enzymatic activity in breast cancer. In ERα-positive MCF-7 cells, HDAC3 knockdown (but not HDAC1 or HDAC2) decreases the level of estrogen receptor α (ERα) mRNA as well as the ERα protein.(177) Moreover, the knockdown of HDAC3 decreases the stability of ERα mRNA, estrogen-mediated cyclin D1 expression, and estrogen-dependent proliferation of ERα-positive MCF-7 cells (Figure 10).(177)

Figure 10

Figure 10. Role of HDAC3 in estrogen-dependent cyclin D1 expression.

Cui et al.(178) showed that HDAC3 expression is negatively associated with the expression of both estrogen receptor (ER) and progesterone receptor (PR) but positively linked with the overexpression of human epidermal growth factor 2 (HER2) along with the clinical condition of breast cancer. Therefore, HDAC3 is considered as a prognostic marker in invasive ductal breast cancer. Kim et al.(179) showed that HDAC3 selectively interacts with CREB3 (HDAC1, HDAC2, and HDAC8 having no interaction) to regulate transcription and migration in metastatic breast cancer. HDAC3 overexpression is found to repress CREB3-enhanced NF-κB activation of XIAP and NR4A2 genes. HDAC3 also selectively suppresses CREB3-mediated CXCR4 transcription in the MDAMB-231 cell line. Therefore, HDAC3 negatively regulates CREB3-modulated transcription and signaling pathways in metastatic breast cancer.
Hu et al.(180) showed that HDAC3 overexpression enhances the programmed death ligand-1 (PD-L1) mRNA levels in both MIA PaCa-2 and BxPC-3 cell lines. Inhibition of HDAC3 by RGFP966 (22) (structure and enzyme inhibition profile is provided in Figure 17) helps to reduce significantly the level of PD-L1 at the transcriptional level in both these cell lines in a dose-dependent fashion along with the disruption of the HDAC3/STAT3/PD-L1 pathway (Figure 11).

Figure 11

Figure 11. HDAC3 inhibition by RGFP966 (22) modulates the disruption of HDAC3/STAT3/PD-L1 pathway.

It has been reported that HDAC3 is overexpressed in glioma cells. The probable involvement of HDAC3 in the development of vasculogenic mimicry (VM)-positive glioma has been proposed by Liu et al.(181) HDAC3 activates PI3K and ERK1/ERK2, which further stimulate pro-MMP-14 and pro-MMP-2 resulting in the activation of MMP-14 and MMP-2, respectively. The activated MMP-2 and MMP-14 further cleave the laminin5γ2 (LAMC2) into promigratory fragments Ln5γ2′ and Ln5γ2x, which are involved in the formation of VM networks in glioma (Figure 12).

Figure 12

Figure 12. Role of HDAC3 to form VM networks in glioma. Adapted with permission from ref (181). Copyright 2015 John Wiley and Sons.

Zhang et al.(182) showed that selective inhibition of HDAC3 by RGFP966 (22) (5 μM and 10 μM) enhances TRAIL-mediated apoptotic cell death in colon cancer through modulating the death receptor 5 (DR5).
McLeod et al.(183) showed that selective inhibition of HDAC3 by RGFP966 (22) (40 mg/kg body weight three times a week for 3 weeks) triggers the inhibition of R1881-induced activation of androgen receptor (AR) genes such as PSA and NKX3-1 in LNCaP prostate cancer cells with an increase in acetylation of histone H3. Therefore, RGFP966 (22) may be useful in the treatment of castration-resistant prostate cancer (CRPC).(183) In hepatocellular carcinoma (HCC), HDAC3 knockdown increases the miR-195 level.(184,185) Moreover, selective inhibition of HDAC3 helps to activate miR-195 via transcription in HCC. Similarly, both HDAC3 mRNA and protein are found to be highly overexpressed in gastric carcinoma (GC).(184,186)HDAC3 knockdown significantly decreases the tumor weight as well as the colony-forming ability of GC cells. Again, HDAC3 inhibition helps in the downregulation of the miR-454 as well as upregulation of the chromodomain helicase DNA-binding protein 5 (CHD5), which could be a fruitful strategy to combat GC. Yin and co-workers(187) demonstrated the overexpression of HDAC3 in cholangiocarcinoma (CCA), and selective inhibition of HDAC3 by MI-192 (23) (structure and enzyme inhibition profile is provided in Figure 17) decreased cellular viability in CCA cell lines (IC50 = 6 μM at 48 h). Moreover, HDAC3 knockdown along with treatment with MI-192 (23) was found to induce the cleavage of poly-ADP ribose polymerase (PARP) as well as p53 expression to promote apoptosis in CCA. Interestingly, MI-192 (23) also inhibited the deacetylation by HDAC3 but not that by HDAC1 and HDAC2. It also effectively inhibited a CCA-xenografted tumor, suggesting it to be a potential therapeutic agent to combat CCA. Nevertheless, HDAC3 overexpression is the self-sufficient reason for poor prognosis in CCA patients.(188) Inhibition of HDAC3 by domatinostat/4SC-202 (17) (Figure 4, Table 3) and BG45 (24) (structure and enzyme inhibition profile is provided in Figure 17) helps decrease cellular viability and colony formation and induces apoptosis. Selective HDAC3 inhibition might be a valuable strategy to combat cutaneous T-cell lymphoma (CTCL). HDAC3-selective inhibitor RGFP966 (22) (at 10 μM for 24 h) increases the acetylation of H3K9/K14, H3K27, and H4K5 in CTCL cell lines HH and Hut78.(189) Due to HDAC3 inhibition by RGFP966, there is an increase in γH2aX, which indicates DNA damage and impeded S-phase cellular proliferation in CTCL. Again, Gupta et al.(190) found a higher level of HDAC3 expression in pSTAT3-positive diffused large B-cell lymphoma (DLBCL). Moreover, knockdown of HDAC3 upregulated the acetylation of STAT3Lys685 but hindered STAT3Tyr705 phosphorylation and inhibited the growth of pSTAT-positive DLBCL cells. According to Narita and co-workers,(191) HDAC3 inhibition by antisense RNA oligonucleotide-induced G2/M phase arrest triggers apoptosis in human maxillary carcinoma (HMC) IM-3 cell line through heating at acidic conditions. Nevertheless, the knockdown of HDAC3 (but not HDAC1 and HDAC2), along with downregulating serine and tyrosine phosphorylation of STAT3, triggers the cleavage of PARP and caspase-3 in multiple myeloma (MM).(136) Treatment with HDAC3-selective inhibitor BG45 (24) showed dose-dependent inhibition in MM cells (1.875 μM to 30 μM for 48 and 72 h) following caspase-3 and PARP-mediated apoptosis (Figure 13). Interestingly, it has also been proven that BG45 (24) does not display any effect on the acetylation of α-tubulin, suggesting its HDAC3 selectivity over HDAC6.

Figure 13

Figure 13. Inhibition of HDAC3 by BG45 (24) modulates the caspase-3 and PARP-mediated apoptotic pathway.

Bone marrow stromal cells (BMSCs) of patients having multiple myeloma are found to modulate a higher level of HDAC3 expression compared to BMSCs of healthy donors.(192) It is interesting to note that HDAC3-selective inhibitor BG45 (24) does not stimulate significant BMSC growth inhibition, but the knockdown of HDAC3 markedly inhibits endothelial tube formation. This suggests that HDAC3 has a critical role in bone marrow endothelial cells (BMECs) for neo-angiogenesis. The knockdown of HDAC3 in BMSC increases the secretion of soluble glycoprotein 130 (sgp130), and subsequently, the IL-1 trans-signaling pathway in multiple myeloma is hindered. HDAC3 knockdown triggers the downregulation of p-STAT3 and p-RB1 along with an increase in p21, without any change in AKT and ERK. Various analyses (such as MTT assay, Western blot, RT-PCR, and immunohistochemistry study) suggest the effective roles of HDAC3 in leukemia.(193) The knockdown or inhibition of HDAC3 decreases IkBα expression as well as expression of TNFα, IL-1β, and IL-18. Inhibition of HDAC3 by TSA (4) helps to trigger the apoptotic signaling pathways through the modulation of BAD, Cyto-C, and Bcl-xL proteins followed by the activation of caspase-3 and caspase-7 in leukemia. Long et al.(164) showed that combined treatment with valproic acid (VPA) (300 mg/kg), doxorubicin (3 mg/kg), and Ara-C (100 mg/kg) administered once daily for 5 days downregulated the expression of HDAC3 in K562/Doxo or THP-1 cells. Interestingly, AKT selectively tethers with HDAC3 but not with other HDACs. Moreover, the deacetylation of Lys20 is crucial for HDAC3-modulated activation of AKT.(194) The knockdown of HDAC3 or selective inhibition by RGFP966 (22) (3 μM for 24 h) enhances AKT acetylation, decreases AKT phosphorylation, and dissociates HDAC3 from AKT. Therefore, HDAC3 inhibition downregulates AKT and sensitizes leukemia cells to cytotoxicity upon treatment with anticancer agents. Moreover, depletion of HDAC3 along with treatment with RGFP966 (22) increases the survival time in acute myeloid leukemia (AML). As per the observation of Xu et al.,(195) SAHA (1) (5 μM for 48 h) downregulates HDAC3 expression, which is related to decreased expression of Bcr-Abl and c-Myc proteins in the BV-173 chronic myeloid leukemia (CML) cell line. Harada et al.(196) showed that HDAC3 knockdown along with HDAC3 inhibition with BG45 (24) (20 μM for 48 h) downregulates DNA methyltransferase 1 (DNMT1) in multiple myeloma. HDAC3 inhibitors stimulate the degradation of c-Myc, which upregulates the expression of DNMT1. Nevertheless, HDAC3 inhibitors by enhancing DNMT1 hyperacetylation decrease its stability. Moreover, the knockdown of HDAC3 significantly reduces the expression of XIAP and Bcl-2 proteins related to apoptosis. Combination therapy with BG45 (24) and DNMT1 inhibitor 5-azacytidine was found to synergistically downregulate DNMT1 to reduce tumor growth and induce apoptosis in multiple myeloma. Lombard et al.(197) further proposed that HDAC3 strongly reduces the level of ETS family transcription factors, ELK1 and ELK3. Again, HDAC inhibitors ameliorate the MAPK pathway inhibitors in BRAF, NRAS, PTEN, and NF1 mutant melanoma. Therefore, combination therapy with BRAF/MEK/HDAC3 inhibitors might be helpful to suppress the genes related to DNA repair, followed by the destruction of melanoma cells. Escaffit et al.(198) demonstrated that proteolytic cleavage of HDAC3 and cytoplasmic relocalization is crucial for apoptosis, whereas forced nuclear localization of HDAC3 reduces apoptotic efficacy. Moreover, the cleavage of HDAC3 increases histone acetylation along with the activation of transcription of pro-apoptotic genes during apoptosis.(199)
He et al.(200) reported that apart from HDAC3 overexpression in colorectal cancer, HDAC3 negatively correlates with A-kinase anchor protein 12 (AKAP12), which is a tumor suppressor in colorectal cancer. TSA (4) and RGFP966 (22) increase the expression of AKAP12 by inhibiting HDAC3. Ma et al.(201) showed that HDAC3 is a target related to the transcription of EWS-FL11. Entinostat (15, Figure 4, Table 3), a dual HDAC1/3-selective inhibitor, inhibited the growth of Ewing sarcoma (ES) cells. Entinostat (15, Figure 4, Table 3) not only arrests cells at G0/G1 phase but also enhances the expression of G1 gatekeeper p21Waf1/Cip1 followed by a decrease of cyclin D1 in ES. It also markedly enhances the ROS level as well as induces caspase-3/caspase-7 activity in TC-71 and CHLA-258 cell lines. Interestingly, the depletion of EWS-FL11 expression results in a marked reduction in cyclin D1 as well as HDAC3 but not in HDAC1. Therefore, it may be postulated that HDAC3 (but not HDAC1) is a downstream regulator of EWS-FL11 expression. Entinostat (15, Figure 4, Table 3) also hyperacetylates HSP90 followed by the depletion of EWS-FL11, BRCA1, BRCA2, and RAD51 proteins in ES cells. Therefore, it may be suggested that ES is dependent on EWS-FL11/HDAC3/HSP90 signaling and combination therapy with entinostat (15) along with inhibitors of HSP90 and PARP and DNA-damaging compounds may be a fruitful strategy to combat ES.(201) In this context, it may be inferred from the above-mentioned discussions that HDAC3 plays crucial roles in modulating a variety of cancers through diverse cellular mechanisms. Though several mechanisms of HDAC3 are still unknown, a number of lines of evidence suggest that selective inhibition of HDAC3 by specific HDAC3 inhibitors such as RGFP966 (22), MI-192 (23) and BG45 (24) may be effective to combat specific cancers. Therefore, HDAC3 is a potential emerging target for designing novel and selective HDAC3 inhibitors as drug candidates for the management of a variety of cancers.

3.2. HDAC3 in Diabetes

HDAC3 may be a key player in modulating diabetes as supported by a number of findings. Three single nucleotide polymorphisms (SNPs) of HDAC3 are found to be correlated with the risk of type-II diabetes in the Chinese population.(202) Moreover, during treatment with BRD3308 (25) (structure and enzyme inhibition profile is provided in Figure 19) in the ZDF rat model of type-II diabetes, there is a selective HDAC3 inhibition that helps to improve plasma glucose level along with a protective effect on pancreatic β-cells.(203) In addition, selective HDAC3 inhibition by BRD3308 (25) (10 μM for 24 h) reduces apoptosis in pancreatic β-cells through a reduction in caspase-3 activity.(204) During inflammatory conditions, HDAC3 expression is promoted by NF-κB, which in turn helps in the reduction of PPARγ activity.(205,206) HDAC3 is associated with inhibitor kappa Bα (IkBα) in cytosol. After the degradation of IkBα, HDAC3 enters the nucleus and inhibits the PPARγ activity through TNFα and subsequently modulates glucose and lipid metabolism.(206) Moreover, HDAC3 inhibition also induces the acetylation of PPARγ as well as stimulates the expression of PPARγ target genes (namely aP2 and adiponectin) and increases insulin sensitivity in type-II diabetes.(207) Apart from that, HDAC3 knockdown or HDAC3 inhibition enhances the stimulation of insulin signaling and glucose uptake. Interestingly, inhibition of HDAC3 was enough to enhance the transcription of PPARγ in the absence of thiazolidinediones. Therefore, a selective HDAC3 inhibitor may be highly effective in combating type-II diabetes by increasing insulin sensitivity without any adverse effects exerted by PPARγ ligands.(207) Further, HDAC3 knockdown was found to restore glucose stimulated insulin secretion (GSIS).(205,208) Meier and Wagner(155) proposed that HDAC1/3 inhibitors have a better effect in pancreatic β-cell apoptosis by distinct reduction of cellular nitrite along with GSIS. However, HDAC1 and HDAC2 inhibitors do not exhibit any protective effect. This suggests that HDAC3 inhibitors might be more beneficial in regulating the pancreatic β-cell apoptosis. Moreover, HDAC3 inhibitors may trigger fibroblast growth factor 21 (FGF21), a crucial modulator of lipid metabolism in the liver, to control the gluconeogenesis along with pancreatic β-cell protection by stimulating oxidative metabolism.(155)
Xu et al.(209) found that HDAC3 activity is markedly enhanced in hearts of diabetic mice and treatment with RGFP966 (22) (10 mg/kg sc every other day for 3 months) decreased cardiac HDAC3 activity. Moreover, RGFP966 (22) treatment helps to prevent diabetes-associated cardiac remodelling by reducing the accumulation of collagen and the expression of connective tissue growth factor (CTGF) and fibronectin-1 (FN-1) in diabetic cardiomyopathy (DCM). RGFP966 (22) treatment also reduces diabetic-induced oxidative stress along with the expression of plasminogen activator inhibitor-1 (PAI-1) and TNF-α in diabetic hearts. The treatment with RGFP966 (22) reversed diabetes-induced insulin resistance in heart as evidenced by the upregulation of insulin receptor substrate-1 (IRS-1) along with AKT phosphorylation, and GLUT4 expression. Nevertheless, treatment with RGFP966 (22) blocked the activation of cardiac ERK1/ERK2 but not that of JNK or p38 MAPK in OVE26 diabetic mice. Again, HDAC3 inhibition enhances the acetylation of histone H3 on the DUSP5 gene promoter region. Therefore, HDAC3 inhibition contributes significantly to the epigenetic modification of the DUSP5–ERK1/2 pathway as a therapeutic approach to combat DCM.(209) All these observations strongly support the crucial roles of selective HDAC3 inhibition as effective antidiabetic therapy. From the above discussions, it is clearly indicated that HDAC3 plays distinct roles in modulating diabetes and related disorders. Selective HDAC3 inhibition by compounds such as RGFP966 (22) and BRD3308 (25) is also effective in controlling diabetes and related cardiomyopathy. Therefore, highly selective HDAC3 inhibitors may be evaluated extensively to identify novel drug candidates as an armament against diabetes.

3.3. HDAC3 in Obesity

As far as obesity is concerned, inactivation of HDAC3 helps to upregulate several genes (such as Acab, Gpam, Elvol3, and Fasn) along with downregulation of several genes (namely, Acads, Acls5, Cpt1b, and Crot) related to lipidogenesis, fatty liver, and lipid oxidation in myocardium.(210−213) Additionally, HDAC3 deletion induces the expression of genes associated with lipid metabolism (such as Scd1 and Scd2), which may be due to the dysregulation of PPAR nuclear receptors.(210) HDAC3 was also found to repress fatty acid oxidation genes by modulating PPAR in intestinal epithelium. HDAC3-selective inhibitor RGFP966 (22) (150 mg/kg po for 8 days) activated the expression of fatty acid oxidation genes, that is, mitochondrial β-oxidation genes and peroxisomal β-oxidation genes in small intestine, as evaluated in C57B2/6 WT mice.(210)HDAC3 deletion in heart also produced severe hypertrophic cardiomyopathy with reduced survival rates in the presence of high fat diet,(213) but complete knock out of HDAC3 was found to be embryonic lethal.(214) HDAC3 also reduced the transcription of phosphoenolpyruvate carboxykinase (PEPCK) by inhibiting PPARγ and CREB. This mechanism clearly highlights crucial roles of HDAC3 in glycerogenesis in adipose tissue and lipodystrophy as tested in aP2-p65 transgenic mice.(215) In the liver, HDAC3 also regulates circadian-mediated lipid metabolism.(205) HDAC3 inactivation in heart and muscle decreases fatty acid catabolism in diet-induced obese (DIO) mice.(213) Not only that, inhibition of HDAC3 helps to restore PPARγ function in obesity. TSA (4) is found to block HDAC3 activity effectively in DIO mice.(205) Though there are not many experimental data, it is clear from the above discussion that HDAC3 has a direct correlation with lipid metabolism through genetic manipulations and hyperactivity of HDAC3 induces obesity. Moreover, selective HDAC3 inhibition by RGFP966 (22) also activates fatty acid oxidation genes, and therefore, HDAC3 can be considered as a novel biomolecular target, and selective HDAC3 inhibition with highly potent inhibitors might be a potential therapeutic strategy to open up a new vista in treating obesity.

3.4. HDAC3 in Neurodegenerative Disorders

A number of studies reveal critical roles of HDAC3 in neurodegenerative disorders. Schmitt et al.(216) demonstrated that HDAC3 plays a crucial role in the death of retinal ganglion cells (RGCs) after acute optic nerve injury. Deletion of HDAC3 in RGCs results in optical nerve crush (ONC)-induced nuclear atrophic characteristics, namely, formation of heterochromatin along with the loss of nuclear structure.(216) Selective HDAC3 inhibition with RGFP966 (22) (2 μM) is found to prevent the above-mentioned nuclear atrophies after ONC.(217) Repeated intraperitoneal administration of RGFP966 (22) reduced the loss of RGCs after ONC without exerting any off-target toxic effects. Therefore, selective inhibition of HDAC3 may be targeted for the treatment of ONC. Norwood and co-workers(218) explained that HDAC3 is crucial for the proper development of the brain. Moreover, depletion of HDAC3 from CNS progenitor cells leads to severe abnormalities in the neocortex and cerebellum and subsequent perinatal death of mice. HDAC3 regulates the activity of glial fibrillary acidic protein (GFAP) at the transcription level. Further, conditional knockout of HDAC3 from neurons of the forebrain resulted in neurological disorders, namely, forepaw clasping, ataxia, and paralysis followed by death. HDAC3 is an important factor related to huntingtin-induced neurodegeneration.(147) HDAC3, liberated from mutant huntingtin, was found to take part in modulating the neurotoxic activity. Knockdown of HDAC3 was found to inhibit mutant huntingtin neurotoxicity, and neurotoxicity is significantly decreased in HDAC3-deficient neurons. HDAC3 inhibitors were found to be effective against Friedreich’s ataxia.(219,220) Xia et al.(221) demonstrated that RGFP966 (22) (15 μM for 1 h) by selective inhibition of HDAC3 reduced LPS-induced proteins in microglia in neurological disorders. Selective HDAC3 inhibition by RGFP966 (22) is supposed to downregulate the STAT3/STAT5 pathway, the Toll-like receptor signaling pathway (namely, TLR2, TLR3, and TLR6), and MAPK p38 and spleen tyrosine kinase (SYK). Selective HDAC3 inhibition by RGFP966 (22) also decreased inflammatory responses in CNS.(184,221) RGFP966 (22) through HDAC3 inhibition decreased TNF-α and IL-6 as well as blocking the activation of STAT3 and STAT5. Therefore, HDAC3 might be a valuable target to combat microglial activation and inflammation of neurodegenerative disease. Jia et al.(222) demonstrated that by selective inhibition of HDAC3, RGFP966 (22) (10 and 25 mg/kg, 3 injections/week sc for 10 weeks) improved the motor deficits and provided neuroprotective effects on striatal volume. However, it did not markedly alter the chemokine and cytokine genetic expression levels but did alter the striatal expression of macrophage migration inhibitory factor (MIF) related to the activation of glial cells in N171-82Q transgenic mice. Moreover, RGFP966 (22) also caused a reduction in glial fibrillary acidic protein (GFAP) immunoreactivity in the striatum of N171-82Q transgenic mice. These observations suggest that inhibition of HDAC3 might be effective in treating Huntington’s disease (HD). Suelves et al.(223) further suggested that HDAC3 has crucial roles in the impairment of long-term memory in HD. RGFP966 (22) by selective inhibition of HDAC3 reduced the activity of HDAC3 in hippocampus and striatum when administered through subcutaneous route in HdhQ7/Q7 wild-type (WT) and HdhQ7/Q111 knock-in (KI) mice. RGFP966 (22) (50 mg/kg sc three times/week for 3 to 6.5 months) was found to prevent or delay the impairment in recognition as well as spatial long-term memory in HD mice. Further, RGFP966 (22) by selective inhibition of HDAC3 in HD mice affects the expression of memory-related genes (such as Arc, Egr1, and c-Fos) essential for maintaining long-term memory and synaptic plasticity. Moreover, treatment with RGFP966 (22) was found to prevent deficits in corticostriatal-dependent motor learning skills. It also stabilized or repressed striatal CAG repeat expansions in HD mice. Not only that, RGFP966 (22) decreased the oligomerization of mutant huntingtin (mHtt) protein in striatum that is a distinctive feature of HD. HDAC3 was found to increase hippocampal-based object regulation and location memory along with drug-related memories.(224−226) By selective HDAC3 inhibition, RGFP966 (22) (30 mg/kg ip) helped to trigger memory in APP/PS1 mice.(224) McQuown and co-workers(227) showed that HDAC3 has pivotal roles in modulating enhanced memory in hippocampal-dependent object recognition. They also showed that the deletion of HDAC3 in the hippocampus might be effective in increasing novel object recognition (NOR). HDAC3-selective inhibitor RGFP966 (22) (10 mg/kg sc) increased hippocampal-dependent object memory.(226) It has also been observed that HDAC3 has an impact in cognitive diseases related to schizophrenia.(139) HDAC3-mediated epigenetic modulation has been found to regulate the inflammatory gene network in microglia after spinal cord injury (SCI).(140) HDAC3 inhibitor RGFP966 (22) suppressed inflammatory responses leading to neuronal protection and enhanced functional recovery in SCI. Moreover, HDAC3 inhibition helps to suppress IFNγ and TNFα, as well as a broad spectrum of inflammatory cytokines, leading to tissue repair in SCI. Additionally, Sanchez et al.(228) showed that selective HDAC3 inhibitor RGFP966 (22) (10 μM for 24 h) enhanced the expression of Arg-1, a well-known anti-inflammatory phenotype (M2) marker, and decreased the formation of foamy macrophages in SCI in vitro. However, the in vivo study revealed that HDAC3 inhibition by RGFP966 (22) (10 mg/kg ip for 3 days) did not exhibit any effect on the functional recovery of macrophage phenotype after SCI. Chen et al.(141) showed that valproic acid (VPA) (300 mg/kg/day ip for 3 days) decreased HDAC3 protein expression without affecting HDAC1 and HDAC2 in an injured or lesioned spinal cord. VPA decreased the HDAC3 activity in the nucleus but not in the cytosol. Therefore, it can be inferred that VPA shows neuroprotective efficacy and decreases HDAC3-mediated inflammatory responses in neurons and microglia in the case of SCI. VPA was found to increase STAT1 and NF-κB p65 acetylation. It also induced marked interactions between NF-κB p65 and STAT1. Subsequently, it inhibited nuclear translocations and DNA-binding ability after SCI. Yang et al.(229) showed that the nuclear localization of HDAC3 markedly decreased in brain ischemic preconditioning (PC) in vivo. By selective blocking of HDAC3, RGFP966 (22) imitated the neuroprotective effects related to PC in vivo after middle cerebral artery occlusion (MCAO). Moreover, knockdown of HDAC3 and inhibition of HDAC3 enhanced the acetylation of histones related to genes Bcl2l1, Hspa1a, and Prdx2, which may be associated with protection in the PC. Therefore, it may be inferred that HDAC3 inhibition helps in the PC of the brain and may be effective in protection against stroke. Spinocerebellar ataxia type-1 (SCA1) is caused by the misregulation of the ataxin-1 (ATXN1) gene, and HDAC3 inhibition may help to modulate ataxin-1 regulation.(122) Selective HDAC3 inhibition might be useful for preventing spinocerebellar ataxia type-7.(122,230) Krishna et al.(231) reported that RGFP966 (22) through the inhibition of HDAC3 hindered the impairment of amyloid-β oligomer-induced synaptic plasticity in CA1 pyramidal neurons, which can be effective in targeting Alzheimer’s disease. Therefore, from the above discussions, it might be inferred that HDAC3 plays crucial roles not only in the development of the brain but also in several neurodegenerative disorders (Huntington’s disease, Friedreich’s ataxia, etc.). Selective HDAC3 inhibition by RGFP966 (22) was also found to be effective in object recognition and memory enhancement. Therefore, it is well validated that potent HDAC3-selective inhibitors should be considered for the management of several neurodegenerative diseases.

3.5. HDAC3 in Rheumatoid Arthritis

HDAC3 plays crucial roles in modulating rheumatoid arthritis (RA). HDAC3 inhibitors reduce the IL-1β-induced expression of a number of modulators of RA, such as MMPs (namely, MMP-1 and MMP-3), interferon-β1 (IFNβ1), chemokines (namely, CCL2-3, CXCL9-11), and interleukins (namely IL-6 and IL-8)(138) (Figure 14). Furthermore, HDAC3 is also established as an epigenetic modulator of inflammation.(232,233)

Figure 14

Figure 14. Role of HDAC3 in arthritis.

HDAC3 also modulates STAT1 phosphorylation required for transcriptional activation. HDAC3 inhibitors inhibit the induction of STAT1 DNA-binding in RA fibroblast like synoviocytes (FLS) in response to IL-1β.(138) The selective inhibition of HDAC3 by MI-192 (23) (10 μM) inhibits the production of TNF along with IL-6 in PBMCs of RA patients.(232) HDAC3 has also a direct relation to osteoarthritis (OA).(234) HDAC3 expression in both nucleus and cytoplasm was markedly reduced in osteoarthritis + moderate intensity treadmill exercise group (OAM) compared to the osteoarthritis group (OAG). Apart from a greater level of ADAMTS5 and NF-κB mRNA, there was also a higher level of HDAC3 mRNA in OAM than in OAG. By inhibiting HDAC3, RGFP966 (22) (50 μM, intraarticular, 3 times/week for 4 weeks) decreased the level of IL-1β stimulation and subsequently NF-κB expression to exert a protective role in OA. Also, RGFP966 (22) by inhibiting HDAC3 selectively inhibited the nuclear translocation of NF-κB. RGFP966 (22) also inhibited ROS production in chondrocytes through inhibition of HDAC3. From the above discussion, it is obvious that HDAC3 plays crucial roles in the modulation of inflammatory mechanisms related to rheumatoid arthritis and osteoarthritis. Selective HDAC3 inhibition by MI-192 (23) and RGFP966 (22) has also been found to be effective in alleviating the symptoms of arthritis. Hence, it might be worth targeting HDAC3 with more potent inhibitors to delineate an effective treatment strategy for arthritis.

3.6. HDAC3 in Cardiovascular Disease and Hypertension

Hoeksema et al.(235) demonstrated that HDAC3 is the only HDAC enzyme having crucial roles in regulating atherosclerotic lesions. They found that deficiency of myeloid HDAC3 triggers deposition of collagen in atherosclerosis and stabilizes plaque phenotype. Moreover, depletion of HDAC3 triggers a soluble macrophage-secreted factor and helps in the production of collagen by vascular smooth muscle cells (VSMCs). In addition, deletion of HDAC3 triggers the upregulation of TGFβ, which stabilizes atherosclerotic lesions. Therefore, HDAC3 may be targeted to improve atherosclerotic conditions in cardiovascular diseases. Lewandowski et al.(236) demonstrated that HDAC3 modulates the epigenetic silencing of TGF-β1 in congenital heart disease. HDAC3 was also found to play crucial roles in hypertension. HDAC3 deacetylates the mineralocorticoid receptor (MR).(151) HDAC3 is the only enzyme among the class I HDACs that modulates the transcriptional activity of MR. Therefore, knockdown of HDAC3 or inhibition of HDAC3 results in reduced transcriptional activity of MR to prevent hypertension.(151)
Along with HDAC1 and HDAC2 levels, HDAC3 level was also found to be increased in a hypoxia-induced pulmonary hypertensive rat model.(237) Moreover, HDAC3 expression was found to be induced in spontaneously hypertensive rats (SHRs).(238) Nozik-Grayck and co-workers(152) showed that histone deacetylation through HDAC3 reduced the expression of extracellular superoxide dismutase (SOD) in pulmonary artery smooth muscle cells (PASMCs), and HDAC3 inhibitors help to protect against idiopathic pulmonary arterial hypertension (IPAH) by enhancing the level of PASMC SOD3 expression. HDAC3 was also found to be overexpressed in an experimental model of heart failure. The reduction of HDAC3 increases cardiac activity and lowers vascular fibrosis.(239,240) Ryu et al.(241) showed that selective HDAC3 inhibitor RGFP966 (22) (3 (mg/kg)/day for 7 days) markedly reduced systolic blood pressure, cardiac hypertrophy, and the thickness of the aortic wall in angiotensin-II-induced hypertensive mice. However, it did not show any effect in modulating eNOS uncoupling and oxidative stress in such mice.
Zhao et al.(242) showed that selective HDAC3 inhibition reduced the infarct volume in mice pretreated with RGFP966 (22) (10 mg/kg) and subjected to ischemia–reperfusion (I/R) injury (DIR-H) compared to untreated mice subjected to I/R injury (DIR). RGFP966 (22) treatment significantly increased SOD activity but reduced the level of malondialdehyde (MDA) and ROS in the DIR-H group compared to the DIR group of mice. HDAC3 inhibition by RGFP966 (22) exerted protective effects on cerebral I/R injury in diabetic mice. Apart from that, HDAC3 inhibition also increased autophagy in diabetic mice with cerebral I/R injury. HDAC3 inhibitor RGFP966 (22) was found to inhibit the diabetes-induced aorta damage by reducing hepatic Kelch-like ECH-associated protein-1 (Keap1) as well as by increasing the nuclear transcription of erythroid 2-related factor (Nrf2) and, subsequently, by increasing the activation of anti-inflammatory genes. HDAC3 inhibition also enhanced the expression of FGF21, which has a protective role in diabetes-induced aorta damage.(184,243) Also, the overexpression of HDAC3 was found to modulate the biosynthesis of cholesterol through repression of lanosterol synthase.(244) In this context, it is evident that HDAC3 is one of the crucial HDAC isoforms, playing pivotal roles in modulating cardiovascular disease and hypertension. Also, selective HDAC3 inhibitors such as RGFP966 (22) help to alleviate hypertensive states and atherosclerotic conditions. Therefore, selective HDAC3 inhibitors can be explored more extensively to identify effective drug candidates for the treatment of cardiovascular and hypertensive disorders.

3.7. Role of HDAC3 in Lung and Kidney Diseases

HDAC3 plays a pivotal role in lipopolysaccharide (LPS)-induced endothelial barrier dysfunction (EBD), which is a key factor in acute lung injury (ALI).(245) HDAC3 activity is enhanced during Ser24 phosphorylation that helps to translocate HDAC3 into the cytosol, where HDAC induces the deacetylation of heat shock protein 90 (HSP90) triggering chaperone activity following the Rho-ROCK pathway.(246) Steroid receptor coactivator (Src) localizes HDAC3 and further activates HSP90 followed by RhoA activity and the subsequent phosphorylation of ROCK protein, which in turn phosphorylates myosin light chain (MLC) to induce EBD. HDAC3-selective inhibitor RGFP966 (22) has been found to exert a protective effect on LPS-mediated ALI and EBD through regulating HSP90. Gu et al.(247) demonstrated that the deficiency of HDAC3 resulted in NF-κB-mediated transcriptional activation along with the overexpression of cytokines and, in turn, enhanced TGF-β/Smad responsible for the development of ALI. HDAC3 also deacetylated endothelial nitric oxide synthase (eNOS) in the cytoplasm and, subsequently, decreased vascular function.(248) HDAC3 helped to deacetylate p65 and subsequently negatively modulated TNF-α-induced luciferase activity, which is inhibited by TSA (4).(137) HDAC3 was also found to regulate IL-1 induced IL-8 or CXCL2 gene expression, as well as the inflammatory signaling, by deacetylating lysine residues 122, 123, 314, and 315 in NF-κB p65.(249) TSA (4) through the inhibition of HDAC3 led to a decrease of monocyte chemoattractant protein-1 (MCP-1) secretion. RGFP966 (22) by selective inhibition of HDAC3 decreased TNF-α-induced chemokine ligand 2 (CCL2).(137,250) By inhibiting HDAC3, RGFP966 (22) reduced cytokine IL-1β, IL-6, and IL-12b activity in macrophages and enhanced expression of anti-inflammatory gene IL-10 in precision-cut lung slices (PCLS) by modulating the transcriptional activity of NF-κB p65.(137,251) Lin et al.(252) showed that selective HDAC3 inhibition increased the acetylation of PPARγ and prevented the loss of Klotho (an antiaging protein expressed in kidney) and helped to retard the development of chronic kidney disease (CKD). As HDAC3 is a modulator of NF-κB-mediated inflammation, HDAC3 inhibitors may be efficacious for the management of chronic obstructive pulmonary disease (COPD) and asthma.(253) Apart from selective HDAC3 inhibition, promoting NF-κB transcriptional activity and siRNA-mediated HDAC3 downregulation also decreased the expression of pro-inflammatory genes (such as IL-1β, IL-6, etc.), which might have beneficial roles in COPD and asthma.(253) Moreover, along with HDAC1 and HDAC2, HDAC3 inhibition decreases pro-inflammatory cytokines in COPD. Entinostat (15) and TSA (4) have been found to effect reduced inflammatory responses in asthma and COPD via HDAC3 inhibition as evidenced by in vivo mouse models.(253) In light of the above-mentioned discussions, it is clearly indicated that HDAC3 has a correlation in the mechanisms associated with lung and kidney diseases, and selective inhibition of HDAC3 may be taken into consideration for the management of lung and kidney disorders.

3.8. HDAC3 in Protozoal and Viral Diseases

HDAC3 has been found to be a key regulator controlling genetic expression and cellular differentiation in apicomplexa Toxoplasma gondii.(254) Selective inhibition of T. gondii HDAC3 (TgHDAC3) by FR235222 increases the level of histone H4 acetylation and might be useful against acute and chronic toxoplasmosis. Regarding the hepatitis C virus (HCV), HDAC3 inhibitor RGFP966 (22) (10 μmol/L for 72 h) reduced the expression of mRNA in HCV replication.(255) Treatment with RGFP966 (10 μmol/L for 72 h) increased the level of liver-expressed antimicrobial peptide-1 (LEAP-1), whereas the level of apolipoprotein-A1 (Apo-A1), which is related to the life cycle of HCV, was decreased. Interestingly, RGFP966 (22) increased histone H3 acetylation around Apo-A1 transcriptional start sites (TSS) though Apo-A1 expression was decreased. Moreover, RGFP966 (22) prevented CCAAT-enhancer-binding protein α (C/EBPα) binding to the LEAP-1 promoter and increased HIF1α and STAT3 in HCV. Therefore, it may be inferred that HDAC3 inhibitors may be promising therapeutic agents against HCV. HDAC3 was also found to repress the transcription of human T-cell lymphocytic virus type-1 (HTLV-1).(256) Additionally, HDAC3 inhibition was found to be crucial for latent HIV-1 reactivation.(159) Interestingly, knockdown of HDAC3 (but not HDAC1 and HDAC2) produced significant cell death along with the reactivation of latent HIV-1 expression. Barton et al.(257) showed that inhibition of HDAC3 by BRD3308 (25) (concentration of 10 μM and greater after 12 h) induced the transcription of HIV-1 as evidenced in the 2D10 cell line. Moreover, treatment with 15 μM BRD3308 (25) overnight also induced the growth of HIV-1 from resting CD4+ T-cells of antiretroviral-treated and aviremic HIV-positive patients. These results suggested that inhibition of HDAC3 may be effective to combat HIV-1 infection. Moreover, HDAC3-selective inhibitors such as RGFP966 (22) and BRD3308 (25) were found to take part in modulating protozoal and viral diseases. Therefore, potent and selective HDAC3 inhibitors might be evaluated to identify novel therapy for the management of these protozoal and viral diseases.

3.9. The Role of HDAC3 in Other Diseases

HDAC3 has recently been found to play a crucial role in regulating the glycerol transporter aquaporin-3 (AQP-3) with p53 transcription factor involved.(258) HDAC3-selective inhibitors are effective in treating skin diseases such as psoriasis where AQP-3 is overexpressed.(258) Kim et al.(259) demonstrated that HDAC3 mediates allergic skin inflammation, namely, the triphasic cutaneous reaction (TpCR) and passive cutaneous anaphylaxis (PCA). HDAC3 has been shown to interact with FcεRIβ protein and with Src family protein Lyn upon antigenic response. This triggers the interaction between HDAC3 and Rac1, which is further responsible for the induction of c-Jun and Sp1. Both c-Jun and Sp1 bind to the MCP1 promoter region to promote the expression of MCP1 and, finally, modulate the allergic skin inflammation process. In another study, Kim et al.(260) demonstrated that DNMT1 is a negative regulator of HDAC3. Downregulation of DNMT1 induced HDAC3 expression and enhanced the expression of adhesion molecules, namely VCAM-1, ICAM-1, and integrin α5, to affect vascular permeability leading to allergic skin inflammation. Indirectly, HDAC3 along with SNAIL was induced by the interaction of transglutaminase II (TGase II) and NF-κB. HDAC3 further demonstrated transcriptional effect on E-cadherin, critically involved in allergic inflammation.(261) It was also found that TSA (4) decreases the recruitment of HDAC3 to the interferon regulatory factor (IRF5) promoter and suppresses IRF5 transcription.(262) HDAC3 is an activator during transcriptional regulation of IRF, which is a crucial factor in systemic lupus erythromatous (SLE). Moreover, IRF5 is also involved in immunological disorders, namely, inflammatory bowel disease, RA, and Sjogren’s syndrome. In addition, HDAC3 expression has been observed to be profound in penile fibrosis as well as in erectile dysfunction related to the bilateral cavernous nerve injury (BCNI). VPA decreases penile HDAC3 expression by lowering TGF-β1 and fibronectin expression in the penis.(263) Thus, inhibition of HDAC3 could be a treatment strategy for these penile disorders. It can be inferred that apart from playing important roles in major disease conditions (such as cancer, diabetes, neurodegenerative, and cardiovascular disorders), HDAC3 has crucial roles in modulating neglected diseases (such as skin diseases, allergy, penile erection, etc.). As there are not many reports, the roles of HDAC3 need to be explored more critically, and inhibition of HDAC3 might emerge as a treatment option for the above-mentioned neglected diseases.

4. HDAC3-Selective Inhibitors

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Considering the importance and the crucial role of HDAC3 in diverse disease conditions, selective HDAC3 inhibition can be considered as a promising therapeutic strategy to combat disease conditions without exerting severe off-target effects. In that context, various potent and selective HDAC3 inhibitors have been discussed in the following sections to understand their importance in various disease conditions.

4.1. Hydroxamates as HDAC3-Selective Inhibitors

Tapadar et al.(264) reported some HDAC inhibitors containing an isoxazole group in the linker region adjacent to the hydroxamate group. The cap region of such compounds was modified with various aryl, heteroaryl, and alicyclic functions. It was interesting to note that the thiazolylphenyl moiety as a cap group (26, Figure 15) resulted in potent and selective HDAC3 inhibition (IC50 = 30 nM) maintaining a minimum of 2-fold selectivity over the other HDACs.

Figure 15

Figure 15. Hydroxamates as potent and HDAC3-selective inhibitors.

Compound 26 was found to be highly cytotoxic against a variety of pancreatic cancer cell lines, namely, Mia Paca-2 (IC50 = 4 μM), HupT3 (IC50 = 1 μM), Panc 04.03 (IC50 = 4 μM), Su.86.86 (IC50 = 1 μM), and BxPC-3 (IC50 = 3 μM).
Neelarapu and co-workers(265) reported some hydroxamates based on arylisoxazole and arylpyrazole moieties as dual inhibitors of HDAC3 and HDAC8. It is interesting to note that the isoxazole compounds exhibited higher HDAC3 selectivity over HDAC8, but the pyrazoles were nonselective inhibitors. Compound 27 (Figure 15) exerted potent and selective HDAC3 inhibition over HDAC8. Compound 27 induced the accumulation of acetylated histone H4 in the differentiated SH-SY5Y neuroblastoma cell line at lower concentration. Compound 27 did not exhibit any cytotoxicity but showed neuroprotective effects from chemical-induced apoptosis in retinoic acid differentiated cell line SH-SY5Y.
Thaler et al.(266) reported some spiro[2H-(1,3)-benzoxazine-2–4′-piperidine]-based hydroxamates as potential HDAC inhibitors. Compound 28 exhibited selective HDAC3 inhibitory activity (IC50 = 65 nM) over the other HDACs (Figure 15). It was also effective in exerting cytotoxicity in cancer cell lines K562 (IC50 = 399 nM), A549 (IC50 = 773 nM), and HCT-116 (IC50 = 477 nM), along with a good pharmacokinetic profile and oral bioavailability.
Thaler et al.(267) further reported a series of spiro[chromane-2,4′-piperidine] derivatives as potential HDAC inhibitors as well as cytotoxic agents against K562, A549, and HCT116 in sub-micromolar concentration. Compound 29 (Figure 15) exhibited potent and selective HDAC3 inhibition (IC50 = 90 nM) over other HDACs. It also displayed potential cytotoxicity against cancer cell lines K562 (IC50 = 0.681 μM), A549 (IC50 = 1.322 μM), and HCT-116 (IC50 = 0.777 μM). Again, compound 29 enhanced histone acetylation in K562 cells in a dose-dependent manner as confirmed by flow cytometry analysis. Compound 29 also enhanced the G0/G1 phase population, followed by a reduction in S and G2/M phase populations with a lower dose, but it increased with a higher dose. In the xenograft model induced with HCT-116 colon cancer, compound 29 was also found to show effective antiproliferative efficacy. Modification at the spiro function along with various substitutions at the piperidine moiety by the same group of researchers yielded another series of compounds.(268) Compounds 30 and 31 (Figure 15) demonstrated potent and selective HDAC3 inhibition (IC50 = 28 nM and 30 nM, respectively) maintaining a minimum of 2-fold selectivity over the other HDACs. Both of them showed potent cytotoxicity in cancer cell lines K562, A549, and HCT116.
Choi et al.(269) reported a triazine analog containing a pyrazole group attached to the hydroxamate moiety through a tetramethylene function (32, Figure 15). It exhibited potent and selective HDAC3-inhibitory activity (IC50 = 7 nM) over the other HDACs. It also showed potent cytotoxic efficacy in a variety of lymphoma cell lines, namely, TMD-8 (GI50 = 3 nM), HBL-1 (GI50 = 30 nM), U2932 (GI50 = 148 nM), RC-K8 (GI50 = 94 nM), and SU-DHL-4 (GI50 = 62 nM), along with good drug metabolism and pharmacokinetics (DMPK) profile. An N-hydroxycinnamamide derivative (33, Figure 15) containing an indole cap group, reported by Zang et al.,(270) resulted in potent HDAC3 inhibitory activity (IC50 = 7.5 nM) that was highly selective over HDAC1, -2, and -6.
Cheng et al.(271) designed and synthesized some indole-based hydroxamates as dual HDAC/BRD4 inhibitors. Compound 34 (Figure 16) was a potent HDAC3 inhibitor (IC50 = 23 nM) maintaining a minimum of 5-fold selectivity over HDAC1 (IC50 = 179 nM) and HDAC2 (IC50 = 118 nM).

Figure 16

Figure 16. Indole-based hydroxamates as potent and HDAC3-selective inhibitors.

A p-fluoro substitution at the benzyl group of compound 34 produced compound 35 (Figure 16). It was 4-fold more potent for HDAC3 (IC50 = 5 nM) compared to compound 34. It was also more than 36-fold HDAC3-selective over HDAC1 (IC50 = 181 nM) and HDAC2 (IC50 = 298 nM). Reduction of a methylene spacer between the indole moiety and hydroxamate function of compound 35 led to the development of compound 36 (Figure 16). Compound 36 was also a potent HDAC3 inhibitor (IC50 = 39 nM) selective over HDAC1 (IC50 = 341 nM) and HDAC2 (IC50 = 517 nM). When the benzyl moiety of compound 34 was replaced with a phenylethyl moiety, compound 37 (Figure 16) was produced. It showed similar HDAC3 inhibitory potency as well as selectivity (HDAC3 IC50 = 28 nM; HDAC1 IC50 = 240 nM; HDAC2 IC50 = 139 nM). A five-methylene spacer group between the indole and hydroxamate moiety, instead of the six-methylene spacer of compound 37, led to the development of compound 38 (Figure 16). Compound 38 was about 3-fold less potent for HDAC3 inhibition (IC50 = 76 nM) than compound 37 though it was also selective over HDAC1 (IC50 = 247 nM) and HDAC2 (IC50 = 538 nM). The p-fluoro substitution at the phenylethyl moiety of compound 38 led to the discovery of compound 39 (Figure 16), which was also a potent and HDAC3-selective inhibitor (IC50 = 17 nM) compared with HDAC1 (IC50 = 259 nM) and HDAC2 (IC50 = 946 nM). Methyl substitution was also tried at the benzyl moiety at ortho, meta, and para positions for compound 34 keeping the six-methylene spacer between the indole and hydroxamate moieties unaltered. That led to the development of compounds 4042 (Figure 16). They were also highly potent HDAC3-selective inhibitors. In the case of the five-methylene spacer between the indole and hydroxamate function, the ortho-methyl, meta-methyl, and para-methyl substitution led to the development of compounds 4345 (Figure 16). They were also potent HDAC3-selective inhibitors. However, compounds with the six-methylene spacer were better HDAC3 inhibitors than the corresponding five-methylene spacer analogs (40 > 43; 41 > 44; 42 > 45). These compounds were found to be cytotoxic against human acute leukemia THP-1 cell line. The best active HDAC3 inhibitor, compound 35, also showed effective cytotoxicity (GI50 = 15.5 μM) though it was less cytotoxic than other compounds in this series (compounds 34, 3739, 4445). Compound 35 was found to acetylate histone H3 but not α-tubulin in THP-1 cell. This proved that compound 35 is a HDAC3-selective inhibitor. Compound 35 effectively reduced the c-Myc level in a dose-dependent fashion. The molecular docking analysis between HDAC3 and compound 35 revealed that the hydroxamate moiety coordinates the Zn2+ ion. Two hydrogen bonds were noticed between the amide group of hydroxamate moiety and His134 and His135. The indole moiety took part in hydrophobic and van der Waals interactions with amino acid residues Phe199 and Phe200, respectively. Moreover, the phenyl group was also found to form hydrophobic interaction with Leu266. The fluorine atom also interacted with Arg266.

4.2. Benzamide-Based HDAC3-Selective Inhibitors

A series of benzamide-derived HDAC3 inhibitors selective over the other HDAC isoforms (HDAC1, HDAC2, HDAC6, HDAC8, and HDAC10) were reported by Chen and co-workers.(272) These compounds were found to be potent and highly selective compared to MS-275. The SAR analysis revealed that the six-methylene linker based benzamide derivative containing triazolophenyl substitution at the meta position of the phenyl group (46, Figure 17) demonstrated highly potent HDAC3 inhibition (IC50 = 120 nM) compared to MS-275 (IC50 = 2311 nM). It was also very highly HDAC3-selective (∼250-fold) over other isoforms of HDAC.

Figure 17

Figure 17. Some benzamide-based HDAC3-selective inhibitors.

Modification of the phenyl ring with a thiazole ring, as well as elimination of the triazole moiety, of compound 46 led to some effective and HDAC3-selective inhibitors (4749, Figure 17). It was interesting to note that the thiazole compounds (47, 49) showed better HDAC3 inhibitory potency than the corresponding phenyl derivative (46) but they were lesser HDAC3-selective. Surprisingly, these compounds were unable to exert any neuroprotective effects.(251) Compound 46 was also evaluated against a panel of pancreatic cancer cell lines (such as BxPC-3, HupT3, Mia Paca-2, Panc04.03, and SU 86.86).(273) It was inactive in almost all the cell lines except in SU 86.86, where it was moderately active (IC50 = 32 μM).
Malvaez and co-workers(226) synthesized a unique benzamide molecule called RGFP966 (22, Figure 17). There is a p-fluoro group attached to the benzamide scaffold. A pyrazole moiety is attached to the benzamide moiety through an unsaturated alkylcarbonyl function. Additionally, the pyrazole group is attached to the terminal phenyl group through another unsaturated alkyl group. It is a highly potent HDAC3 inhibitor (IC50 = 80 nM) with a high degree of selectivity over all other HDACs (IC50 > 15000 nM). Various in vitro and in vivo studies have been conducted with RGFP966 (22) as a reference molecule due to higher HDAC3 inhibitory potency and high degree of selectivity. Boissinot et al.(274) synthesized a potent HDAC3 inhibitor, MI-192 (23, Figure 17), with an IC50 of 16 nM and selectivity over several other HDACs (HDAC1, -4, -6, -7, and -8) but not over HDAC2 (IC50 = 30 nM). MI-192 (23, Figure 17) was screened against a panel of cancer cell lines, namely, non-small-cell lung, ovarian, colon, CNS, breast, prostate, renal, melanoma, and leukemia lines. In all these cancer cell lines, MI-192 (23) was found to be cytotoxic at low micromolar concentration. Interestingly, it exhibited better efficacy than MS-275 (15) only in leukemia cell lines; however, it showed lower efficacy in the rest of the cell lines compared to MS-275 (15). Nevertheless, MI-192 (23) was found to promote apoptosis in leukemia cell lines HL60, U937, and Kasumi-1 in a dose-dependent manner. Moreover, it was found to promote leukemia cell differentiation as evidenced by the formation of vacuoles and granules in cytoplasm. Therefore, MI-192 (23) may be effectively targeted to treat leukemia. Minami and co-workers(136) synthesized another unique benzamide derivative BG45 (24) containing a pyrazine scaffold (Figure 17). It is also a highly potent HDAC3 inhibitor (IC50 = 289 nM) exerting a high degree of selectivity over HDAC1, HDAC2, and HDAC6. BG45 (24) is also considered as a reference molecule for conducting various in vitro and in vivo experiments.
Suzuki et al.(275) synthesized 504 aryl cap containing triazole derivatives using the click chemistry approach. Out of these, 59 benzamide compounds inhibited 90% of HDAC3 activity at a dose of 10 μM. However, 48 hydroxamate derivatives inhibited 60% of HDAC3 activity at 1 μM dose. Among the 107 compounds, 11 benzamide derivatives were found to exhibit HDAC3 selectivity over HDAC1 and HDAC2. Two compounds (50 and 51, Figure 17) resulted in potent and selective HDAC3 inhibition (IC50 = 240 nM and IC50 = 260 nM, respectively) having exceptional selectivity over HDAC1, HDAC4, HDAC6, and HDAC8. The molecular docking study(275) of compound 50 with HDAC3 (PDB 4A69) suggested that this compound coordinated with the catalytic Zn2+ ion through amino and carbonyl groups (Figure 18).

Figure 18

Figure 18. Molecular docking interaction of compound 50 with HDAC3 (PDB 4A69). Coordination with Zn2+ ion is shown in dotted orange line. Hydrogen bonding interactions are shown in dotted green arrow.

It also formed two hydrogen bonding interactions with His134 and Gly143 with the amino group and amide group, respectively. The phenyltriazole moiety extended toward the hydrophobic tunnel of HDAC3 formed by the amino acid residues Phe144, Phe200, and Leu266. The terminal thienyl group of compound 50 showed hydrophobic interactions with Pro23 and Phe144. The triazole moiety was geometrically oriented in such a fashion that proper hydrogen bonding interaction could take place for exerting higher HDAC3 inhibition. Both these compounds were found to induce acetylation of NF-κB in HCT116 colon cancer cells evaluated through Western blot analysis. Moreover, the p53 acetylation level was not enhanced by the compounds compared to SAHA (1). These results strongly suggested that the compounds selectively inhibited HDAC3. Moreover, the compounds did not elevate α-tubulin acetylation, which is a parameter for HDAC6 inhibition. Compared to SAHA (1), both compounds exhibited better cytotoxicity against colon cancer cell line HCT116 and prostate cancer cell line PC3. Compounds 50 and 51 markedly repressed HIV-1 expression in latent HIV-1 infected OM 10.1 cells, which suggested that the HDAC3 inhibitors in combination with other anti-HIV agents might be useful in targeting HIV inhibition.
Marson et al.(276) designed and synthesized a series of heterocyclic cap group containing benzamides as potent and HDAC3-selective inhibitors. Replacement of the pyridopyrimidine cap group of the nonselective HDAC inhibitor mocetinostat/MGCD0103 (16, Figure 4) with a phenylimidazolinone moiety led to the development of a potent HDAC3 inhibitor (52, Figure 19) selective over HDAC1, HDAC2, HDAC6, and HDAC8.

Figure 19

Figure 19. Benzamide-based, potent, and HDAC3-selective inhibitors.

The corresponding (S)-phenyl analog (53, Figure 19) containing a thiazoline moiety in place of the imidazolinone scaffold was a highly potent and HDAC3-selective inhibitor (IC50 = 12 nM) maintaining more than 7-fold selectivity over the above-mentioned HDACs. The molecular docking study(276) of the thiazoline derivative 53 with HDAC3 (PDB 4A69) showed that the carbonyl group adjacent to the benzyl moiety and the amine group of the benzamide moiety coordinated the catalytic Zn2+ ion. The benzylamide linker spacer was properly accommodated by a bigger hydrophobic tunnel surrounded by amino acid residues Phe144, Phe200, and Leu266. The cap group containing phenyl and thiazoline moieties showed an interaction with Phe199. Compound 53 displayed good physicochemical properties including higher solubility as well as weak cytochrome P450 inhibitory profile. Compound 53 also showed effective cytotoxicity against various cancer cell lines, namely, A549 (IC50 = 5.78 μM), DU145 (IC50 = 6.40 μM), HCT116 (IC50 = 2.17 μM), and MCF-7 (IC50 = 5.43 μM). However, the imidazolinone derivative 52 exhibited comparatively lower cytotoxicity in HCT116 (IC50 = 18.2 μM) and MCF-7 (IC50 = 30.1 μM) without showing much cytotoxicity in the other two cell lines (IC50> 50 μM). Again, compound 53 enhanced acetylation of H3 on lysine 9 (H3K9Ac) in HeLa and Jurkat cell lines. Interestingly, compound 52 enhanced H3K9Ac in Jurkat but not HeLa cell line at the dose used. Moreover, the flow cytometry analysis revealed that compound 53 enhanced the sub-G1 DNA level in Jurkat cells for apoptosis induction. However, compound 53 induced apoptosis in the G2/M phase in the HeLa cell line. Interestingly, compound 53 also induced apoptosis in Jurkat cells by PARP degradation mediated by caspase-3.
Further, Marson and co-workers(277) reported some highly HDAC6-sparing HDAC3-selective benzamide compounds containing chiral oxazoline cap groups. Compound 54 (Figure 19) containing m-fluorophenyl substitution at the fourth position of the oxazoline group exhibited potent HDAC3 inhibition (IC50 = 24 nM) having a minimum of 10-fold selectivity over the other HDACs. Moreover, aryl substitution at the fourth or fifth position of the oxazoline moiety favored HDAC3 inhibition. The compound having 4,5-diphenyl substitution at the oxazoline scaffold (55, Figure 19) displayed the highest HDAC3 inhibition (IC50 = 6 nM) having a minimum of 18-fold selectivity over the other HDACs. Compound 54 enhanced H3 acetylation in U937 and PC3 cell lines. Nevertheless, flow cytometry analysis revealed that compound 54 increased the sub-G1 DNA content in PC-3 but not in U937 cell line. Additionally, the compounds exhibited DNA accumulation in the G0/G1 phase in U937 cells. Interestingly, compound 54 significantly reduced cyclin E expression in U937 but not in the PC-3 cell line.
Wagner and co-workers(204) structurally modified CI-994 (56, Figure 19) with various substituents and designed some benzamide derivatives. Fluoro substitution at the para position of the benzamide group of CI-994 (56, Figure 19) resulted in BRD3308 (25, Figure 19) which is a highly potent HDAC3 inhibitor (IC50 = 64 nM) maintaining about 17-fold selectivity over HDAC1 and HDAC2. The molecular docking study suggested that BRD3308 (25) had no effect on conformational changes of Leu133 at the HDAC3 active site (PDB 4A69). Both CI-994 (56) and BRD3308 (25) reduced cytokine-induced caspase-3 activity and suppressed β-cell apoptosis in rat INS-1E insulinoma cells. Moreover, CI-994 (56) and BRD3308 (25) also enhanced H3 acetylation in INS-1E cells. The inhibition of HDAC3 activity by both CI-994 (56) and BRD3308 (25) was found to protect β-cells in glucolipotoxic conditions and subsequently to protect rat and human islets. BRD3308 (25) also restored insulin secretion along with a reduction of ROS due to endoplasmic reticulum (ER) stress in INS-1E cells. Moreover, it was also found that HDAC3 (not HDAC1 and HDAC2) was markedly dysregulated in the islets of type-II diabetes patients. It was also noticed that HDAC3-selective inhibition by BRD3308 (25) did not produce thrombocytopenia, whereas HDAC1 and HDAC2 inhibition did produce such toxic effects. This indicated that HDAC3-selective inhibition by BRD3308 (25) was devoid of off-target toxicity. Therefore, HDAC3-selective inhibitors of this type might be useful not only for increasing insulin secretion but also for protecting β-cells from apoptosis, as well as overcoming β-cell glucolipotoxicity in type-II diabetes patients.
Li et al.(278) reported some indole-based arylcarboxamido benzamides as promising HDAC inhibitors. Most of these benzamides displayed potency and selectivity toward HDAC1. Interestingly, only one indole-based arylcarboxamide compound (57, Figure 19) containing a pentamethylene spacer and a p-fluoro group substituted at the benzamide group exhibited potent HDAC3 inhibitory effects (IC50 = 110 nM) with a minimum of 5-fold selectivity over HDAC1 and HDAC2, along with sparing HDAC4, HDAC6, and HDAC8 inhibition.
Hsieh et al.(279) designed a series of benzamide-derived HDAC3-selective inhibitors from pan-HDAC inhibitor AR-42 (58, Figure 19). All these compounds were designed by altering the hydroxamate moiety with a benzamide scaffold along with modification of the aryl cap group and linker function of AR-42 (58). Most of the newly designed molecules were highly potent and HDAC3-selective inhibitors over HDAC1 and HDAC2. They also established that these compounds were not effective in the alteration of tubulin acetylation as well as Notch1, which strongly suggested that these compounds were not effective as HDAC6 and HDAC8 inhibitors. The SAR analysis(279) revealed that fluoro substitution at the para position of the benzamide group yielded potent HDAC3-selective inhibitors. A pyridyl group in place of the phenyl group at the linker function yielded higher HDAC3 inhibitory potency, but HDAC3 selectivity was reduced. Nevertheless, depending on the type of aryl cap group and the related substituents, HDAC3 inhibitory activity and selectivity was found to be altered. Compounds 59 and 60 (Figure 19) were the most effective and selective HDAC3 inhibitors in this series. However, MTT assay revealed that both these compounds were moderately effective in breast cancer cell line MDA-MB-231 (IC50 ≥ 10 μM). Moreover, both the compounds were found to be highly effective in inhibiting colony and mammosphere formation. Western blot analysis further suggested that the compounds downregulated AKT phosphorylation along with β-catenin expression with an increase in H3 acetylation. At 100 mg/kg oral dose, compound 60 mimicked the suppression of HDAC3 depletion of breast tumorogenecity in MDA-MB-231-induced animal model. Therefore, such HDAC3 inhibitors may be targeted for the effective treatment of triple negative breast cancer (TNBC).
McClure et al.(280) reported substrate-driven HDAC3-selective inhibitors. The benzofuran compound with m-fluoro substitution at the benzamide moiety (61, Figure 19) yielded highly potent and 15-fold HDAC3-selective inhibitory activity (IC50 = 80 nM) over HDAC1 and HDAC2. However, 3,4-difluoro substitution at the benzamide moiety (62, Figure 19) yielded 2-fold reduction in HDAC3 inhibition (IC50 = 170 nM) compared to the earlier one, but the selectivity was improved to 34-fold. Compound 62 showed induction of NF-κB p65 and p53 acetylation level without showing any inductive effect on H3/H4 and tubulin acetylation. Also, compound 62 decreased NO production in LPS-induced RAW264.7 cells along with inhibition of high mobility group box protein 1 (HMGB-1) secretion from activated macrophage cells. Combining these observations, it is inferred that HDAC3-selective inhibition may be utilized for the treatment of inflammatory diseases. Compound 62 had the ability to reduce the nuclear localization of HDAC3, which was not observed for SAHA (1). This suggested that compound 62, due to HDAC3-selective inhibitory property, was involved in alterations of cellular localization, p53 acetylation, and regulation of gene transcription to exert anti-inflammatory responses.
Ocasio et al.(281) reported two ferrocene-based benzamide analogs with potent and HDAC3-selective inhibitory activity. Compound 63 (Figure 20A) with a tetramethylene linker/spacer between two carboxamide moieties demonstrated potent HDAC3 inhibition (IC50 = 606 nM) having a minimum of 15-fold selectivity over other HDACs. However, pojamide (64, Figure 20A) with a hexamethylene linker unit showed improved HDAC3 inhibition by more than 6.5-fold (IC50 = 90 nM) compared to compound 63. Again, compound 64 possessed more than 12-fold HDAC3 selectivity over the other HDACs.

Figure 20

Figure 20. (A) Ferrocene-based benzamides as potential HDAC3 inhibitors. (B) Molecular docking interaction of compounds 63 and 64 with HDAC3 (PDB 4A69). Coordination with Zn2+ ion is shown in dotted orange line. Hydrogen bonding interactions are shown in dotted green arrow. (C) 2-Aminobenzamides as effective HDAC3 inhibitors. (D) Effective HDAC3-selective proteolysis targeting chimera (PROTAC) containing benzamide as ZBG.

Both these compounds were docked into the active site of HDAC3 (PDB 4A69). The free amine group of pojamide (64, Figure 20B) coordinated the catalytic Zn2+ ion. It also displayed effective hydrogen bonding interactions with His134 and Asp170. Moreover, the adjacent amide group of the phenyl group formed a hydrogen bonding interaction with the carbonyl function of Gly143. The other amide group adjacent to the ferrocenyl group formed a hydrogen bonding interaction with the carbonyl group of Asp93. The docked structure of compound 63 was slightly different from that of pojamide (64, Figure 20B). Due to the tetramethylene carbon unit, it did not extend properly toward the Zn2+ ion. Therefore, the ligand-binding interactions were slightly shifted. The free amine group, instead of zinc-binding, formed a hydrogen-bonding interaction with Gly143. The carbonyl group associated with the benzamide scaffold interacted with the Zn2+ ion. The differences in the interaction clearly pointed out the better activity and selectivity of pojamide (64) over compound 63. It was also interesting to note that due to steric clashes with Tyr100, Lys33, and the ferrocenyl moiety, pojamide (64) did not bind effectively to the active site of HDAC8 (PDB 1T69). This might be the reason for HDAC3 selectivity of the ferrocenyl compounds. It was interesting to note that pojamide (64) showed equipotent HCT116 cytotoxicity (GC50 = 8.6 μM) compared to HDAC3-selective inhibitor RGFP966 (22) (GC50 = 8.9 μM). Pojamide (64) also increased the acetylated H4K12 level, but compound 63 did not show any effect. Again, pojamide (64) exhibited 90% HCT116-cellular invasion. Nevertheless, pojamide (64) along with sodium nitroprusside reduced the pH2AX level with DNA damage, which may be fruitful in combating colon cancer.
Trivedi and co-workers(282) reported a series of 2-aminobenzamides as effective HDAC3 inhibitors. The compounds were designed by structural modifications of both CI-994 (56) and BG45 (24). Three compounds (6567, Figure 20C) were found to be more than 5-fold HDAC3-selective over HeLa nuclear extract (rich in HDAC1 and HDAC2). Apart from that, these three compounds exhibited better HDAC3 inhibition compared to both BG45 (24) and CI-994 (56). The SAR analysis revealed that aminophenyl or aminobenzyl group attached to the pyrazine moiety is necessary for imparting HDAC3 inhibitory potency. Compound 65 showed better antiproliferation activity against B16F10 melanoma and HeLa cell lines compared to CI-994 (56) and BG45 (24). Compound 65 also showed the highest apoptosis as evidenced by annexin V FITC/PI assay in B16F10 melanoma. Moreover, the cell cycle analysis suggested that compound 65 significantly arrested the G2/M phase cell growth in the B16F10 cell line.
A series of HDAC targeting proteolysis targeting chimeras (PROTACs) containing a benzamide ZBG was synthesized by Cao and co-workers.(283) Only one HDAC-PROTAC (68, Figure 20D) exhibited HDAC3 selectivity (IC50 = 1100 nM) over HDAC1 (IC50 = 3600 nM) and HDAC2 (IC50 = 4200 nM). Compound 68 mediated the degradation of HDAC3 (DC50 = 3200 nM). It was also found to trigger E3 ligase-mediated ubiquitination and subsequent HDAC3 degradation regulated by proteasome. Compound 68 did not show any significant effect on pro- and anti-inflammatory gene transcription. However, the combination of both compound 68 and cereblon (CRBN) ligand pomalidomide was found to downregulate NF-κB p65 in RAW264.7 macrophages.

4.3. Hydrazide-Based HDAC3-Selective Inhibitors

Wang et al.(109) reported a series of benzoylhydrazide derivatives as potent and selective HDAC3 inhibitors. The p-bromo analog (69, Table 4) exhibited potent HDAC3 inhibition (IC50 = 190 nM) with a minimum of 2.5-fold selectivity over the other HDACs.
Table 4. Benzoylhydrazides as Potent and Selective HDAC3 Inhibitors
   IC50 (nM)
compdR1R2HDAC1HDAC2HDAC3HDAC6HDAC8
69Brn-butyl460133019090902830
70OMen-butyl19102520430aa
71t-butyln-butyl1901040706830490
72Brn-propyl170038802204630a
a

Not determined.

A compound with methoxy substitution at the R1 position (70, Table 4) exhibited potent HDAC3 inhibition (IC50 = 430 nM) with about 4.5-fold HDAC3 selectivity over the other HDACs. Interestingly, the t-butyl analog (71, Table 4) yielded the maximum HDAC3 inhibition (IC50 = 70 nM) with more than 2.5-fold HDAC3 selectivity over the other HDACs. Again, the n-propyl analog (72, Table 4) exhibited potency similar to that of the corresponding n-butyl analog (69, Table 4) but the n-propyl analog (72, Table 4) was about 8-fold HDAC3 selective over the other HDACs. Compound 69 strongly inhibited the deacetylation at H4K5 in the HCT116 cell line but did not exhibit any effect on α-tubulin acetylation. It was found to increase the acetylation level of p53 in HCT116 cell line. It also induced acetylation of H2B, H3, and H4. In cell cycle analysis, compound 69 was found to block G2/M phase in a dose-dependent manner. It also activated the p53 and Rb tumor suppressor pathways and suppressed the MYC, MYNC, and KRAS oncogenic pathways. Therefore, inhibitors of this type might be useful in anticancer therapy.
McClure and co-workers(284) reported some hydrazide derivatives as potential HDAC3 inhibitors with promising cytotoxicity against acute myeloid leukemia (AML) compared to solid tumors. The SAR analysis suggested that compounds with smaller alkyl substitution at the hydrazide function resulted in better HDAC3 selectivity compared to the compounds with longer alkyl functions, though all showed higher affinity toward HDAC3. Interestingly, the alkyl chain length should possess three to four carbon units to exert higher HDAC3 inhibition as well as selectivity. Compound 73 (Figure 21) resulted in potent and HDAC3-selective inhibition (IC50 = 1 nM) having a minimum of 12-fold selectivity over HDAC1 and HDAC2 and selectivity for AML over HEK293.

Figure 21

Figure 21. Arylhydrazides as potent and HDAC3-selective inhibitors.

However, an extension of alkyl chain length further by one carbon unit, resulting in n-butyl analog 74 (Figure 21) led to a 4-fold decrease in HDAC3 inhibition (IC50 = 3.7 nM) though compound 74 exhibited a minimum of 16-fold selectivity over HDAC1 and HDAC2 and for AML over HEK293. Elimination of the unsaturated linker from compound 73 resulted in compound 75 (Figure 21), which had reduced HDAC3 inhibitory activity (IC50 = 3.5 nM) with a minimum of 4-fold selectivity over HDAC1 and HDAC2. The same phenomenon was observed for compound 76 (Figure 21), which was also 2-fold HDAC3-selective over the other HDACs. The molecular docking study revealed that compound 73 perfectly fitted into the HDAC3 active site (PDB 4A69). The propylhydrazide moiety entered a narrow tunnel at the active site, whereas SAHA (1) was found to fit into the active site in a completely different orientation. Compound 73 was further evaluated against an array of leukemia and myeloma cell lines. Compound 73 was found to be extremely cytotoxic against the leukemia cell lines, such as MV4-11 (EC50 = 36.37 nM), Molm14 (EC50 = 76.64 nM), and K562 (EC50 = 2160 nM) but comparatively inactive in multiple myeloma cell line RS4-11 (EC50> 10000 nM). Compounds 73, 75, and 76 (Figure 21) enhanced the level of acetylated histones H3 and H4 compared to SAHA (1) as evidenced by the Western blot analysis. Therefore, hydrazide-based HDAC3 inhibitors of this type might prove efficient in the treatment of AML.
Recently, Li et al.(285) designed some new indole cap containing HDAC3 inhibitors selective over HDAC1, HDAC2, and HDAC6. The carboxamidobenzyl derivative having an n-propylhydrazide moiety (77, Figure 22) resulted in potent HDAC3 inhibition (IC50 = 8.5 nM) with a minimum of 7.5-fold selectivity over HDAC1, HDAC2, and HDAC6.

Figure 22

Figure 22. Indole cap containing hydrazides as potent and HDAC3-selective inhibitors.

However, an increase in the alkyl side chain, that is, in the butylhydrazide function, led to the development of compound 78 (Figure 22), which is a 2-fold less potent HDAC3 inhibitor (IC50 = 16.5 nM) than the former one. Compound 78 maintained a minimum of 3-fold HDAC3 selectivity over these HDACs. The SAR observation revealed that a linear alkyl chain length with three to four carbon units should be optimum for maintaining potent HDAC3 inhibitory activity as well as selectivity. Keeping the n-propylhydrazide moiety unaltered, alteration of the linker spacer moiety on HDAC3 inhibition was also monitored. Replacement of the carboxamidobenzyl moiety (compound 77) with carboxamidophenyl group (79, Figure 22) increased HDAC3 inhibition 6-fold (IC50 = 1.4 nM) with a minimum of 7-fold selectivity over the other class I HDACs along with sparing class II HDAC inhibition. Similarly, the carboxamido moiety with long chain linear alkyl functions such as n-pentyl (80, Figure 22), n-hexyl (81, Figure 22), and n-heptyl (82, Figure 22) resulted in highly potent and HDAC3-selective inhibition with IC50 values of 12.4 nM, 5.2 nM, and 12.1 nM, respectively. The molecular docking study of compound 77 (Figure 23) with the HDAC3 catalytic site (PDB 4A69) suggested that the carbonyl function adjacent to the hydrazide moiety coordinated the catalytic Zn2+ ion.

Figure 23

Figure 23. Molecular docking interaction of compound 77 with HDAC3 (PDB 4A69). Coordination with Zn2+ ion is shown in dotted orange line. Hydrogen bonding interactions are shown in dotted green arrow.

Moreover, compound 77 was also found to accept hydrogen bonds from the side chain of amino acid Tyr298. One amide function of the hydrazide moiety donated a hydrogen bond to Gly143, whereas the other amide function of that moiety donated a hydrogen bond to Asp170 and simultaneously accepted a hydrogen bond from His135. The two other amide functions were found to donate hydrogen bonds to Asp93 at the HDAC3 catalytic site, whereas the indole amide function donated hydrogen bonds to backbone amino acid Arg265. It was noticed that compound 79 inhibited MV4-11 leukemia cell line (EC50 = 34.7 nM) and prostate cancer PC-3 cell line (EC50 = 351 nM) in lower concentrations. The Western blot analysis revealed that compound 79 cleaved pro-caspase-3 with a subsequent enhancement of cleaved caspase-3 as well as cleaved PARP, indicating its ability to modulate caspase-dependent apoptosis in the MV4-11 cell line. Moreover, the cell cycle analysis suggested that compound 79 induced sub-G1 cellular arrest in the MV4-11 cell line and G2/M cellular arrest in the PC-3 cell line. Further, compound 79 degraded p53 and subsequently depleted the antiapoptotic proteins c-FLIP and XIAP in the MV4-11 cell line, suggesting the induction of cellular apoptosis.
Li et al.(286) reported some hydrazide compounds depending on the scaffolds of panobinostat (3). Almost all these compounds were found to be potent and selective toward HDAC3 compared to HDAC1, -2, and -6. Initially, the hydroxamate function of panobinostat (3) was replaced with n-propylhydrazide moiety and the amide function of the linker moiety was substituted. Compound 83 (Figure 24) bearing a t-butoxy group displayed potent HDAC3 inhibition (IC50 = 16.8 nM) maintaining a minimum of 10-fold selectivity over HDAC1, HDAC2, and HDAC6.

Figure 24

Figure 24. Panobinostat-based hydrazides as potent and HDAC3-selective inhibitors.

Omission of the t-butoxy substitution at the amide group of linker function led to the discovery of compound 84 (Figure 24), which is about 60-fold more potent (IC50 = 0.3 nM) than 83. It also maintained a minimum of 18-fold HDAC3 selectivity over other HDACs. However, esterification (85, Figure 24) reduced the HDAC3 inhibition drastically, though this compound was also HDAC3 selective. Therefore, it may be postulated that alkyl substitution at the hydrazide moiety is responsible for HDAC3 inhibitory potency and selectivity. Replacement of the indolylethyl group of panobinostat (3) with a benzyl group produced compound 86 (Figure 24), which was a potent HDAC3 inhibitor (IC50 = 6.1 nM), but it showed only 2.5-fold HDAC3 selectivity over HDAC1. However, compound 87 (Figure 24) including a di-n-propyl group instead of an n-propyl group substituted at the terminal amide function resulted in more or less similar potency and selectivity compared to compound 83. Importantly, compound 84 was also found to be a more potent and HDAC3-selective inhibitor than both panobinostat (3) (IC50 = 2.1 nM) and entinostat (15) (IC50 = 77.18 nM). Compound 84 displayed anticancer activity that is p53- and FLT3-status dependent. In wt-p53 FLT-ITD cell line MV4-11, it was found to cleave the pro-caspase 3 and induce apoptosis. It indirectly inhibited the FLT3 pathway through downregulation of FLT3, STAT5, and pERK, which may be effective in combating AML. It also reduced antiapoptotic proteins c-FLIP and XIAP followed by cleavage of pro-caspase 3. Again, compound 84 was found to induce autophagic mechanisms in p53 MV4-11 cells. Moreover, the combination of compound 84 and bortezomib synergistically triggered the pro-caspase 3 cleavage. Noticeably, compound 84 was less genotoxic than panobinostat (3). Further, the bioavailability and pharmacokinetic profile of compound 84 was better than those of panobinostat as evidenced by better half-life (t1/2) and higher AUC values.
Xiao et al.(287) reported some HDAC3-specific PROTACs based on compound 88 (Table 5), which is also a potent and HDAC3-selective inhibitor (IC50 = 13 nM).
Table 5. HDAC Inhibitory Profile of New PROTACs
   IC50 (nM)
compdmnHDAC1HDAC2HDAC3
88  728213
892 9040038
90 56501550350
91 715001420550
Among these CRBN-based PROTACs with PEG linkers, compound 89 (Table 5) exhibited potent HDAC3 inhibition (IC50 = 38 nM) with selectivity over HDAC1 and HDAC2. However, the HDAC3 inhibitory potency was reduced by 10–15-fold for VHL-based PROTACs. Compounds 90 and 91 (Table 5) displayed good HDAC3 inhibition having more or less similar selectivity pattern compared to compound 89. Importantly, compound 90 was found to induce HDAC3 degradation in MDA-MB-468 cells in a dose-dependent fashion (DC50 = 42 nM) without showing any significant changes in protein levels of HDAC1, -2, and -6. Nevertheless, HDAC3 degradation induced by compound 90 was also time-dependent (70% HDAC3 was degraded within 8 h). Apart from that, compound 90, in a dose-dependent manner, enhanced histone acetylation moderately compared to CRBN-based PROTACs. It reflected the selective pattern of HDAC3 degradation conferred by compound 90.

4.4. Modified Benzamide-Based HDAC3-Selective Inhibitors

A series of 2-substituted modified benzamides were designed and synthesized as potent and highly selective HDAC3 inhibitors by Liu and co-workers(288) by using parallel medicinal chemistry (PMC) libraries. Compound 92 (Figure 25) bearing a 2-methylaminobenzamide scaffold resulted in potent HDAC3 inhibition (IC50 = 41 nM) having 366-fold selectivity over HDAC1 sparing other HDACs.

Figure 25

Figure 25. Modified benzamide derivatives as potent and highly HDAC3-selective inhibitors.

Modification of the 2-methylaminobenzamide scaffold with the 2-methylthiobenzamide group led to the development of the most selective inhibitor (93, Figure 25) of this series. It was also a highly potent HDAC3-selective inhibitor (IC50 = 29 nM) with 690-fold HDAC3 selectivity over HDAC1. It spared HDAC2 along with HDAC4, -5, -6, -7, -8, and -9 as well as maintaining a minimum of 69-fold selectivity over HDAC10 and HDAC11. On the other hand, the respective cyclopropyl derivative (94, Figure 25) was also a highly potent and selective HDAC3 inhibitor (IC50 = 170 nM). Keeping the methylthiobenzamide moiety unaltered, modification of the terminal naphthyl group with 2-methoxy-3-quinolinyl moiety also yielded a potent and HDAC3-selective inhibitor (95, Figure 25). Interestingly, compound 93 and other 2-substituted modified benzamide analogs are supposed to bind the catalytic Zn2+ ion of HDAC3 in a monodentate fashion. However, the HDAC3 selectivity of these compounds is probably due to the induced fitting of the 2-substituents in the binding pocket formed by the flipping of the catalytic Tyr305 residue.

4.5. Ethylketones as HDAC3-Selective Inhibitors

Kinzel et al.(289) reported some ketone-based selective class I HDAC inhibitors. Compound 96 (Figure 26) containing an oxazole ring and a dimethylaminoisopropyl moiety was a potent HDAC3 inhibitor (IC50 = 0.6 nM). Compound 96 also displayed a minimum of 6-fold HDAC3 selectivity over HDAC1 (IC50 = 3.5 nM) and HDAC2 (IC50 = 5.3 nM).

Figure 26

Figure 26. Ethylketones and nicotinamides as effective HDAC3 inhibitors.

Modification of the dimethylaminoisopropyl group with a 5-thiazolyl moiety, the oxazole ring with an imidazole ring, and the ethylcarbonyl group with methylaminocarbonyl function produced compound 97 (Figure 26) showing a 40-fold loss in HDAC3 inhibition (IC50 = 24 nM) compared to compound 96. However, compound 97 was more HDAC3-selective over HDAC1 and HDAC2 compared to 96. Again, further modification of compound 97 with 4-pyrazolylphenyl and indole-3-yl ethyl groups (98, Figure 26) decreased the HDAC3 inhibition (IC50 = 42 nM), but the HDAC3 selectivity was increased. Similar highly selective molecules were developed when the 4-pyrazolylphenyl moiety of compound 98 was replaced with a p-dimethylaminophenyl group (99, Figure 26). Cyano substitution at the sixth position of the indole moiety of compound 99 yielded highly potent HDAC3-selective inhibitor 100 (IC50 = 26 nM). It was interesting to observe that the compounds with methylaminocarbonyl moiety resulted in less potent but more HDAC3-selective inhibitors compared to compounds with the ethylcarbonyl moiety. Compound 100 (Figure 26), the most HDAC3-selective inhibitor in this series (selectivity a minimum of 50-fold) also showed good stability in both plasma and hepatocytes of mouse and human.

4.6. Nicotinamides as HDAC3-Selective Inhibitors

Hamoud and co-workers(290) recently designed and synthesized some N-(4-(2-arylidenehydrazine-1-carbonyl) phenyl) nicotinamide derivatives as potent and HDAC3-selective inhibitors. Pyridine being a bioisostere of benzene, the benzamide ZBG group was replaced with the m-pyridyl carboxamide ZBG function. The N-acylhydrazone moiety was selected as the linker function linking the aryl or heteroaryl surface recognition cap functionality and the m-pyridyl carboxamide ZBG. Compound 101 (Figure 26) having a p-tolyl cap group demonstrated potent HDAC3 inhibition (IC50 = 694 nM) with about 7-fold selectivity over pan-HDACs. Replacement of the cap group with o-nitrophenyl group (102, Figure 26) slightly decreased the activity (IC50 = 887 nM), but the selectivity remained almost the same. Compound 101 resulted in the highest anticancer activity against B16F10 melanoma (IC50 = 4.66 μM), whereas compound 102 yielded the best antiproliferation activity against MCF7 breast cancer (IC50 = 7.90 μM) without any toxicity to normal HEK-293 cell line. The best active compound 101 was subjected to molecular docking with HDAC3 enzyme (PDB 4A69). The carbonyl group adjacent to the pyridyl moiety coordinated the Zn2+ ion at the active site (Figure 27).

Figure 27

Figure 27. Molecular docking interaction of compound 101 with HDAC3 (PDB 4A69). Coordination with Zn2+ ion is shown in dotted orange line; hydrogen bonding interactions are shown in dotted green arrow; π–π stacking interactions are shown in dotted blue line.

Also, the carbonyl group accepts a hydrogen bond from active site residues His134 and His135. Moreover, the adjacent amide group formed a hydrogen bonding interaction with Gly143. The N-benzoylhydrazone linker fitted properly into the active site hydrophobic channel having a π–π stacking interaction with His172. Also, the p-tolyl cap group formed a π–π stacking interaction with Phe199 (Figure 27). These compounds passed Lipinski’s criteria for being drug-like candidates and showed low blood–brain barrier (BBB) permeability with no interaction with CYP2D6.

4.7. HDAC3-Selective Inhibitors Derived from Natural Compounds

Wang et al.(291) reported some thailandepsin analogs as potent HDAC3 inhibitors highly selective over the other HDACs. Romidepsin/FK228 (18, Figure 28) was a highly potent HDAC3 inhibitor (IC50 = 18 nM), whereas thailandepsin A (103, Figure 28) showed about a 5-fold less potent HDAC3 inhibition (IC50 = 87 nM).

Figure 28

Figure 28. Thailandepsin analogs and natural products as potent and HDAC3-selective inhibitors.

However, it was also a highly HDAC3-selective inhibitor over the other HDACs. Interestingly, thailandepsin B (104, Figure 28) with a slight structural difference (presence of butyl function in place of methylthioethyl group) was 5-fold better than thailandepsin A (103, IC50 = 23 nM) and comparable to romidepsin/FK228 (18). However, the corresponding reduced compounds produced nonselective HDAC inhibition. The NCI-60 anticancer drug screening and COMPARE analysis revealed that all the compounds possessed a broad spectrum of antitumor efficacy against diverse cancer cell lines. However, their efficacy was better in colon cancer, renal cancer, and melanoma than in leukemia. Thailandepsin A (103) was more potent in most of the cancer cell lines in terms of GI50 value. However, in terms of TGI and LC50 values, it was only found better in particular cell lines, namely, HCC-2998 colon cancer, A498, and RXF393 renal cancer, as well as UACC-62 and LOXIMVI melanoma cell lines.
Li et al.(292) designed, synthesized, and biologically screened some largazole analogs as potent HDAC3 inhibitors selective over HDAC1, HDAC2, and HDAC9. Largazole (105, Figure 28), a naturally occurring macrocyclic depsipeptide was reported by Taori and co-workers(293) as a potential anticancer agent that was further synthesized, biologically screened, and extensively studied by various group of researchers.(294−298) Largazole (105) was a potent and selective HDAC1 inhibitor (IC50 = 146 nM) having a minimum of 4-fold selectivity over the other HDACs.(292) Interestingly, elimination of the heptacarbonyl function of largazole to form a free thiol group as well as modification of the 4-methylthiazoline function with a tetrazolylmethyl function led to the development of compound 106 (Figure 28), which was a highly potent and HDAC3-selective inhibitor (IC50 = 31 nM) with a minimum of 3-fold selectivity over the other HDACs.
Terracciano et al.(299) synthesized some cyclotetrapeptide HDAC inhibitors from naturally occurring HDAC inhibitor FR235222. Among the compounds, compound 107 (Figure 28) was a potent HDAC3 inhibitor (IC50 = 24.7 nM) exerting a minimum of 3-fold selectivity over the other HDACs.

5. Dual HDAC1/3 and HDAC3/6 Selective Inhibitors

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It was interesting to observe that a number of compounds have both potent HDAC3 and HDAC1 inhibitory activity but selectivity over HDAC2 or other HDACs. Nevertheless, many such potential dual HDAC1/3 inhibitors have an effective role in combating various cancers and related diseases. A few compounds also exert dual HDAC3/6 selective inhibition. In this context, it should be mentioned that such compounds may also be utilized as a starting compound for designing selective HDAC3 inhibitors. Effective modification of these molecules either through intuitive design or by robust SAR and molecular modeling analysis may be able to generate newer selective HDAC3 inhibitors. Therefore, in this section, such dual HDAC1/3 and HDAC3/6 selective inhibitors have been discussed.

5.1. Hydroxamates as Dual HDAC1/3 Selective Inhibitors

Zhang and co-workers(300) reported an indole-based N-hydroxycinnamide compound (108, Figure 29, Table 6) exhibiting potent dual HDAC1/3 inhibitory activity selectively over HDAC2 and HDAC6.

Figure 29

Figure 29. (A) Hydroxamate-based dual HDAC1/3 inhibitors. (B) Benzamide-based dual HDAC1/3 inhibitors. (C) Hydrazide-based dual HDAC1/3 inhibitors. (D) Romidepsin-based dual HDAC1/3 selective inhibitors. (E) Dual HDAC3/6 selective inhibitors.

Table 6. Compounds Having Dual HDAC1/3 and HDAC3/6 Inhibitory Activity
   IC50 (nM)
compdRR′HDAC1HDAC2HDAC3HDAC6HDAC8
108(300)-CH(n-propyl)2OMe3901420280940 
109(270)p-OMePhOMe17.559.57.187 
110(165)p-ClPhH11.8498.13.9308.2 
111(165)p-FPhH16.74573.5101.7 
112(165)p-OMePhH6413.63.2185.6 
113(301)5-(dimethylamino)naphthalene-1-sulfonyl24.7106.724.4365.9 
114(301)2-methoxy-PhNHCO 4.819.55.9294.2 
115(302)p-OMeBnz 2501800120 720
116(303)H 9833097a1900
117(304)Me 150760370 5000
118(278)p-OMePhCO-indole-3-ylmethyl58.629642.9  
119(109)-NMe2n-butyl2308801209570720
120(109)t-butyln-butyl1901040706830490
121(109)p-OMePhCO-n-pentyl29.8332.110.9>100000 
122(286)Boc 28.8278.612.6>50000 
123(286)H 29.4107.519.9>50000 
124(286)-NHBnz 15.867.56.12>50000 
125(286)-OBnz 56.3174.624.8>50000 
126(305)SH(CH2)2CH═CH-i-Pr2.236.69.84592550
127(305)SH(CH2)2CH═CH-H2.8457.73313550
128(306)-CO(CH2)6CO- 8961130342.61260
a

97% at 10 μM.

Compound 108 (Figure 29A, Table 6) demonstrated better antiproliferative efficacy compared to SAHA (1) in a diverse set of cancer cell lines including U937, PC3, A549, ES-2, HCT116, and MDA-MB-231. In a U937 xenograft model, compound 108 displayed promising in vivo tumor growth inhibition (TGI = 53%, T/C = 42%) with no significant loss of body weight and no toxicity in liver and spleen. Replacement of the di-n-propyl function of compound 108 with a p-methoxyphenyl group led to the discovery of compound 109 (Figure 29A, Table 6), which was also a highly potent dual HDAC1/3 selective inhibitor.(270) It also showed better antiproliferative activity compared to SAHA (1) when evaluated in 5 different cancer cell lines (namely, MOLT-4, HEL, K562, HeLa, and PC-3). A slight modification of compound 109 resulted in some highly potent dual HDAC1/3 selective inhibitors (110112, Figure 29A, Table 6).(165) Due to a high degree of structural similarity with compounds 108 and 109, these compounds (110112) also displayed better cytotoxicity in various cancer cell lines (namely, U937, K562, HEL, HL60, MDA-MB-231, PC-3, MCF-7, HCT116, and A549) compared to SAHA (1). These compounds (110112) significantly enhanced the level of acetylated histones H3 and H4. Compounds 110 and 111 dose-dependently induced 61.76% and 64.25% cellular apoptosis, respectively, in the U937 cell line, which was better than SAHA (1) (26.83%). Compound 110 exhibited potent oral antitumor efficacy of 55.10% in a xenograft model of female BALB/c-nu mice.
In another study, Zhang and co-workers(301) reported some hydroxamates as effective HDAC inhibitors. Compound 113 (Figure 29A, Table 6) containing a 5-(dimethylamino) naphthalene-1-sulfonyl group at the cap position displayed effective HDAC1/3 dual inhibitory activity. Replacement of this group with 2-methoxyphenylaminocarbonyl function (114, Figure 29A, Table 6) produced a 5-fold improvement of both HDAC1 and HDAC3 inhibition. Both of these compounds exerted dual HDAC1/3 inhibition that was selective over HDAC2 and HDAC6. These compounds also exhibited potent cytotoxicity against various cancer cell lines, namely, U937, K562, HL60, MCF-7, MDA-MB-231, and PC3. Compound 113 (Figure 29A) exhibited 53.57% tumor growth inhibition in a U937 cell-based xenograft model, which is better than SAHA (1) (24.97%), at 100 (mg/kg)/day dose. It also showed effective HDAC inhibition with enhanced tubulin acetylation level. Compound 113 also reduced the level of p-Erk and c-Raf proteins in the U937 cell line with a decrease in pAKT level.
Abdelkarim and co-workers(302) designed, synthesized, and evaluated some amine-based HDAC inhibitors. Compound 115 (Figure 29A) containing an indole group attached to the p-methoxybenzyl function demonstrated potent dual HDAC1/3 inhibitory efficacy selectively over HDAC2 and HDAC8. Taha et al.(303) reported a tetrahydroisoquinoline-based hydroxamate derivative with hexamethylene group (116, Figure 29A) that showed dual HDAC1/3 inhibitory activity selectively over other HDAC isoforms.

5.2. Benzamides as Dual HDAC1/3 Selective Inhibitors

Keeping the linker moiety unaltered, Chou et al.(304) modified the structure of SAHA (1) by replacing the phenyl cap group with a p-tolyl group and the hydroxamate ZBG group with a benzamide moiety to produce the pimelic diphenylamide HDAC inhibitor (117, Figure 29B). Compound 117 was found to be a potent HDAC1/3 inhibitor selective over other HDAC isoforms (Table 6) sparing HDAC4, -5, and -7 (IC50 > 180 μM). Xu et al.(220) further established that compound 117 not only induces H3 histone acetylation but also specifically binds to HDAC3 to activate the expression of FXN gene as well as increase the level of frataxin protein in Friedreich’s ataxia (FRDA). Li et al.(278) reported an indole-based arylcarboxamido benzamide derivative (118, Figure 29B, Table 6) having potent dual HDAC1/3 inhibitory activity selective over HDAC2.

5.3. Hydrazides as Dual HDAC1/3 Selective Inhibitors

A benzoylhydrazide derivative containing an n-butyl group attached to the hydrazide function and a dimethylamino group substituted at the para position of the phenyl ring was found to be potent dual inhibitor of HDAC1/3 inhibitor (119, Figure 29C, Table 6) selective over HDAC2, HDAC6, and HDAC8.(109) A t-butyl group in place of the dimethylamino function produced an equipotent dual HDAC1/3 inhibitor (120, Figure 29C, Table 6) selective over other HDACs. Compound 119 was found to exert potent cytotoxicity against cancer cell lines HepG2 (IC50 = 1.5 μM), HCT116 (IC50 = 3.5 μM), MDA-MB-231 (IC50 = 7.2 μM), and HCC1957 (IC50 = 35.9 μM). Similarly, an indole cap containing benzoylhydrazide derivative (121, Figure 29C, Table 6) with an n-pentyl group attached to the hydrazide function demonstrated highly potent dual HDAC1/3 inhibitory activity selective over HDAC2 and HDAC6.
Li et al.(286) reported a series of para-substituted benzoylhydrazide derivatives where the hydrazide function was attached to the n-propyl group. The 2-methyl-indole-3-ylethyl derivatives (122 and 123, Figure 29C, Table 6) were highly potent dual inhibitors of HDAC1/3 selective over HDAC2 and HDAC6. Replacement of the 2-methyl-indole-3-ylethyl function with both aminobenzyl and methoxybenzyl groups yielded highly potent dual inhibitors of HDAC1/3 selective over HDAC2 and HDAC6 (124 and 125, Figure 29C, Table 6).

5.4. Romidepsin-Based Dual HDAC1/3 Selective Inhibitors

Yao et al.(305) reported some romidepsin-derived derivatives (126 and 127, Figure 29D, Table 6) as potent dual HDAC1/3 inhibitors highly selective over other HDAC isoforms.

5.5. Dual HDAC3/6 Selective Inhibitors

Soumyanarayanan and co-workers(306) reported a hydroxamate derivative (128, Figure 29E, Table 6) having a unique dual HDAC3/6 selectivity profile over other HDACs. The molecular docking study suggested that due to the orientation of Asn197 residue, there is a preferable conformation of the loop to interact with compound 128. In the case of HDAC1 and HDAC2, there is a glutamic acid residue in place of Asn197 of HDAC3. This suggests the reason behind compound 128 being more selective toward HDAC3. Two additional amino acid residues, Asp675 and His676 (not present in HDAC1, -2, and -3) are observed in the loop of HDAC6 that provides the loop more flexibility to effectively interact with compound 128. This may be the reason for the exceptional potency of compound 128 toward HDAC6. Apart from exerting potential cytotoxicity against breast cancer cell lines MDA-MB-231 (EC50 = 6.3 μM) and MCF-7 (EC50 = 7.3 μM), compound 128 also resulted in potent cytotoxicity against multiple myeloma cell lines KMS-12BM (EC50 = 7.6 μM), H929 (EC50 = 4.6 μM), and OPM2 (EC50 = 7.9 μM) and acute myeloid leukemia cell line MOLM14 (EC50 = 2.8 μM). Compound 128 also responded well in the apoptosis assay in MDA-MB-231 cell line. The levels of histone H3 acetylation as well as tubulin acetylation were found to be enhanced markedly by treatment with compound 128, suggesting the potency toward both HDAC3 and HDAC6.

6. Future Perspectives

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In this Perspective, the role of HDAC3 in various disease conditions (cancer, inflammation, rheumatoid arthritis, neurodegenerative and CNS disorders, cardiovascular diseases, diabetes, and parasitic and viral infection) has been discussed in detail. A variety of HDAC3 inhibitors such as hydroxamates, benzamides, and modified benzamides, as well as hydrazides, has also been discussed in regards to their HDAC3 inhibitory potency and selectivity over other HDACs. A number of results have established HDAC3 as a potential biomolecular target for design and development of selective HDAC3 inhibitors to combat these disease conditions. Though it has been established that HDAC3 is a potential therapeutic target to combat multiple disease conditions, less attention has been paid to strategies for designing HDAC3-selective inhibitors. In this context, it was noticed that only a few molecular modeling studies have been performed on the existing HDAC3 inhibitors. Probably, the lack of availability of both active and HDAC3-selective inhibitors may be responsible for hindering the drug discovery processes. However, the strategies for designing HDAC3 inhibitors are mostly confined to either intuitive design or enzyme–ligand interactions. Earlier, our group performed a QSAR/QAAR analysis on the available benzamide-derived HDAC3 inhibitors to acquire knowledge linking the important structural and physicochemical aspects of the compounds and the respective bioactivity.(307) A total of 24 models were developed: 8 models developed on HDAC3 inhibitory activity, 8 models constructed on HDAC3 selectivity over HDAC1, and 8 models developed on HDAC3 selectivity over HDAC2. Regarding these QSAR models on HDAC3 inhibitory activity, it was noticed that the steric features and polar character of these molecules may be necessary for improving HDAC3 inhibition. As far as the HDAC3 inhibitory activity over HDAC1 is concerned, it was observed that the benzamide moiety along with smaller electron withdrawing fluorine atom may be crucial for maintaining the HDAC3 selectivity. However, the molecular size and shape as well as less polarity and less hydrophobicity are crucial factors for retaining HDAC3 selectivity over HDAC2. Our group further performed(308) a robust molecular modeling technique (3D-QSAR, CoMFA, and CoMSIA, as well as Bayesian classification) on 113 benzamide-based HDAC3 inhibitors. This study further justified and validated our earlier observation(307) that the benzamide moiety along with electron withdrawing fluorine substitution may attribute some favorable steric effect for enhancing HDAC3 inhibition and selectivity. This study also demonstrated that the hydrophobicity and steric character at the linker moiety favor activity. The activity is reduced whenever groups of these types are substituted at the cap position and at the terminal zinc binder moieties. Nevertheless, the amide function is found to be responsible for Zn2+ chelation. The free amino group of the benzamide scaffold may act as a hydrogen bond donor feature. Apart from such modeling techniques, various other computational methodologies (ligand-based and structure-based) may be taken into consideration for designing more active and selective HDAC3 inhibitors. Apart from that, the crystal structure of HDAC3 will also help to reveal the important ligand–receptor interactions essential for both the activity and the selectivity. Therefore, not only the ligand-based and structure-based design strategies, but also the intuitive design strategies may be beneficial for the drug discovery processes related to HDAC3. Extensive studies have been made on the molecular mechanisms on HDAC3 inhibitors. These studies are still going on. However, there is a lack in the discovery of novel potential and HDAC3-selective inhibitors. This Perspective, in a nutshell, provides a thorough idea not only about the role of HDAC3 in disease conditions but also about a diverse set of HDAC3-selective inhibitors. This will hopefully benefit researchers to identify potential HDAC3-selective inhibitors.

Author Information

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  • Corresponding Authors
  • Author
    • Nilanjan Adhikari - Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, P.O. Box 17020, Kolkata, 700032 West Bengal, IndiaOrcidhttps://orcid.org/0000-0001-5523-7716
  • Author Contributions

    The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

  • Notes
    The authors declare no competing financial interest.

Biographies

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Nilanjan Adhikari

Nilanjan Adhikari is currently working as an assistant professor in the Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India. He has completed his B.Pharm. (2007), M.Pharm. (2009) and Ph.D. (2018) degrees from Jadavpur University, Kolkata. He pursued his doctoral and postdoctoral research under the guidance of Prof. Tarun Jha in the Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India. His research area includes design, synthesis, and evaluation of anticancer small molecules, especially inhibitors of zinc-dependent metalloenzymes. He is also working on drug design of different bioactive molecules through rigorous computational modeling techniques including quantitative structure–activity relationship (QSAR) analyses. He has published 85 research or review articles in different reputed peer-reviewed journals including eight book chapters.

Tarun Jha

Tarun Jha, a faculty member of the Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India, has supervised 16 Ph.D. students and guided eight research projects funded by different organizations. He has published more than 150 research articles in different reputed peer-reviewed journals. His research area includes design and synthesis of anticancer small molecules. Prof. Jha is one of the members of the Academic Advisory Committee of the National Board of Accreditation (NBA), New Delhi, India.

Balaram Ghosh

Balaram Ghosh earned B.Pharm. (1998) and M.Pharm. (2000) in Pharmaceutical chemistry from the Department of Pharmaceutical Technology, Jadavpur University, Kolkata. He earned a Ph.D. from the Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan (2009), and worked as a postdoctoral research fellow at Harvard Medical School, Boston, Massachusetts, from 2009 to 2013. Dr. Ghosh joined as an assistant professor in the Department of Pharmacy, BITS-Pilani, Hyderabad campus, in 2013 and has served the institution to the present. The main research interest of his lab includes the development of subtype specific histone deacetylase inhibitors or activators as epigenetic modulators. He has altogether 87 publications, 11 national patents (filed), and 4 international patents (published). He has synthesized BG45, a histone deacetylase 3 inhibitor, which is commercialized by Sigma-Aldrich (Merck).

Acknowledgments

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Nilanjan Adhikari is grateful to the Council of Scientific and Industrial Research (CSIR), New Delhi, India, for providing research associateship (RA) [File No. 09/096(0966)/2019-EMR-I, Dated 28-03-2019]. The research has been supported by the research fund provided by the Council of Scientific and Industrial Research (CSIR-37(1722)/19/EMR-II) to Balaram Ghosh. Tarun Jha is also thankful for the financial support from RUSA 2.0 of UGC, New Delhi, India, to Jadavpur University, Kolkata, India. The authors are thankful to Tarun Kumar Patel and Sravani Pulya of BITS Pilani, Hyderabad Campus, India, as well as Suvankar Banerjee and Sandip Kumar Baidya of Jadavpur University, Kolkata, India, for their assistance. The authors are thankful to the Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India, and the Department of Pharmacy, BITS-Pilani, Hyderabad, India, for providing the research facilities.

Abbreviations Used
AD

Alzheimer’s disease

AKAP95

A-kinase anchor protein 95

AKT

protein kinase B

ALI

acute lung injury

ALS

amyotrophic lateral sclerosis

BMEC

bone marrow endothelial cells

BMSC

bone marrow stromal cells

CCA

cholangiocarcinoma

CDK

cyclin-dependent kinase

c-FLIP

cellular FLICK-like inhibitory protein

CKD

chronic kidney disease

COPD

chronic obstructive pulmonary disease

CREB

cAMP-response element binding protein

CRPC

castration-resistant prostate cancer

CTCL

cutaneous T-cell lymphoma

CTGF

connective tissue growth factor

CXCR4

C-X-C chemokine receptor type 4

DAD

deacetylation activating domain

DCM

diabetic cardiomyopathy

DLBCL

diffused large B-cell lymphoma

DNMT1

DNA methyltransferase 1

DR

death receptor

EBD

endothelial barrier dysfunction

EGFR

epidermal growth factor receptor

ELK

ETS-like protein

eNOS

endothelial nitric oxide synthase

ERα

estrogen receptor α

ERK

extracellular signal-regulated kinase

ES

Ewing sarcoma

ETS

E26 transformation-specific

FLIP

Flice inhibitory protein

GFAP

glial fibrillary acidic protein

GSIS

glucose stimulated insulin secretion

HAT

histone acetyltransferase

HCC

hepatocellular carcinoma

HDAC

histone deacetylase

HD

Huntington’s disease

HER2

human epidermal growth factor 2

HID

histone interacting domain

HIF-1α

hypoxia inducible factor-1α

HP1

heterochromatin protein 1

HTLV-1

human T-cell lymphotropic virus type-1

HSP90

heat shock protein 90

IAP2

inhibitor of apoptosis 2

ICAM1

intracellular adhesion molecule 1

IFN-γ

interferon-γ

IL

interleukin

IPAH

idiopathic pulmonary arterial hypertension

IRF

interferon regulatory factor

IRS-1

insulin receptor substrate-1

JNK

c-Jun N-terminal kinase

Keap1

kelch-like ECH-associated protein 1

LPS

lipopolysaccharide

MAPK

mitogen-activated protein kinase

MDD

major depressive disorder

MCL-1

myeloid cell leukemia sequence 1

MEF

myocyte enhancer factor

MHC

major histocompatibility complex

MLC

myosin light chain

MM

multiple myeloma

MMP

matrix metalloproteinase

MR

mineralocorticoid receptor

N-CoR

nuclear receptor co-repressor

NES

nuclear export signal

NF-κB

nuclear factor κB

Nrf2

nuclear transcription of erythroid 2-related factor

ONC

optic nerve crush

PAI-1

plasminogen activator inhibitor-1

PARP

poly-ADP ribose polymerase

PASMC

pulmonary artery smooth muscle cell

PBMC

peripheral blood mononuclear cell

PCA

passive cutaneous anaphylaxis

PD

Parkinson’s disease

PDL-1

programmed death ligand-1

PEPCK

phosphoenolpyruvate carboxykinase

PI3K

phosphoinositide 3-kinase

PPAR

peroxisome proliferator-activated receptor

PTM

post-translational modification

RECK

reversion-inducing cysteine-rich protein with Kazal motifs

RAR

retinoic acid receptor

RGC

retinal ganglion cell

ROS

reactive oxygen species

RXR

retinoid X receptor

Rpd3

reduced potassium dependency 3

SCA1

spinocerebellar ataxia type-1

SCI

spinal cord injury

Sir2

silent information regulator 2

SIRT

sirtuin

STAT

signal transducer and activator of transcription

SMRT

silencing mediator of retinoic acid thyroid receptor

SLE

systemic lupus erythromatous

SNP

single nucleotide polymorphism

SOD

superoxide dismutase

SYK

spleen tyrosine kinase

TBP2

thioredoxin binding protein

TGF-β1

transforming growth factor-β1

TIMP

tissue inhibitor of matrix metalloproteinase

TNBC

triple-negative breast cancer

TNF-α

tumor necrosis factor-α

TpCR

triphasic cutaneous reaction

TRAIL

tumor necrosis factor-related apoptosis-inducing ligand

VDR

vitamin D receptor

VEGF

vascular endothelial growth factor

VM

vasculogenic mimicry

VSMC

vascular smooth muscle cell

XIAP

X-linked inhibitor of apoptosis

ZNF-UBP

zinc-finger ubiquitin binding domain

References

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  • Abstract

    Figure 1

    Figure 1. Lysine deacetylation of histone proteins catalyzed by HDAC.

    Figure 2

    Figure 2. Different classes of HDACs.

    Figure 3

    Figure 3. HDAC inhibitors in modulating diverse biological conditions.

    Figure 4

    Figure 4. Approved and clinically evaluated HDAC inhibitors.(76−107)

    Figure 5

    Figure 5. (A) Structure of HDAC3 (PDB 4A69) [A chain, indigo; B chain, yellow; C chain, red; D chain, green; zinc ions are shown as magenta spheres; [Ins(1,4,5,6)P4] is located in the interface of A, B and C chains shown as scaled ball and stick model]. (B) Intermolecular interactions of zinc, acetate and surrounding amino acids at A chain. (C) Intermolecular interactions of zinc, acetate, and surrounding amino acids at B chain.

    Figure 6

    Figure 6. Potential HDAC inhibitors used to evaluate the binding pattern and orientation with several HDACs

    Figure 7

    Figure 7. Structures of docked TSA (4, green), SK-683 (19, purple), and CG-1521 (20, cyan) in the active sites of HDAC1 (a), HDAC2 (b), HDAC3 (c), and HDAC8 (d) (left) and their top views in these proteins with surface representations (right). Reprinted with permission from ref (132). Copyright 2005 American Chemical Society.

    Figure 8

    Figure 8. Structures of docked SAHA (1, blue), MS-275 (15, red), and NVP-LAQ824 (21, yellow) in the active sites of HDAC1 (a), HDAC3 (b), and HDAC8 (c). Reprinted with permission from ref (132). Copyright 2005 American Chemical Society.

    Figure 9

    Figure 9. Role of HDAC3 in various disease conditions.

    Figure 10

    Figure 10. Role of HDAC3 in estrogen-dependent cyclin D1 expression.

    Figure 11

    Figure 11. HDAC3 inhibition by RGFP966 (22) modulates the disruption of HDAC3/STAT3/PD-L1 pathway.

    Figure 12

    Figure 12. Role of HDAC3 to form VM networks in glioma. Adapted with permission from ref (181). Copyright 2015 John Wiley and Sons.

    Figure 13

    Figure 13. Inhibition of HDAC3 by BG45 (24) modulates the caspase-3 and PARP-mediated apoptotic pathway.

    Figure 14

    Figure 14. Role of HDAC3 in arthritis.

    Figure 15

    Figure 15. Hydroxamates as potent and HDAC3-selective inhibitors.

    Figure 16

    Figure 16. Indole-based hydroxamates as potent and HDAC3-selective inhibitors.

    Figure 17

    Figure 17. Some benzamide-based HDAC3-selective inhibitors.

    Figure 18

    Figure 18. Molecular docking interaction of compound 50 with HDAC3 (PDB 4A69). Coordination with Zn2+ ion is shown in dotted orange line. Hydrogen bonding interactions are shown in dotted green arrow.

    Figure 19

    Figure 19. Benzamide-based, potent, and HDAC3-selective inhibitors.

    Figure 20

    Figure 20. (A) Ferrocene-based benzamides as potential HDAC3 inhibitors. (B) Molecular docking interaction of compounds 63 and 64 with HDAC3 (PDB 4A69). Coordination with Zn2+ ion is shown in dotted orange line. Hydrogen bonding interactions are shown in dotted green arrow. (C) 2-Aminobenzamides as effective HDAC3 inhibitors. (D) Effective HDAC3-selective proteolysis targeting chimera (PROTAC) containing benzamide as ZBG.

    Figure 21

    Figure 21. Arylhydrazides as potent and HDAC3-selective inhibitors.

    Figure 22

    Figure 22. Indole cap containing hydrazides as potent and HDAC3-selective inhibitors.

    Figure 23

    Figure 23. Molecular docking interaction of compound 77 with HDAC3 (PDB 4A69). Coordination with Zn2+ ion is shown in dotted orange line. Hydrogen bonding interactions are shown in dotted green arrow.

    Figure 24

    Figure 24. Panobinostat-based hydrazides as potent and HDAC3-selective inhibitors.

    Figure 25

    Figure 25. Modified benzamide derivatives as potent and highly HDAC3-selective inhibitors.

    Figure 26

    Figure 26. Ethylketones and nicotinamides as effective HDAC3 inhibitors.

    Figure 27

    Figure 27. Molecular docking interaction of compound 101 with HDAC3 (PDB 4A69). Coordination with Zn2+ ion is shown in dotted orange line; hydrogen bonding interactions are shown in dotted green arrow; π–π stacking interactions are shown in dotted blue line.

    Figure 28

    Figure 28. Thailandepsin analogs and natural products as potent and HDAC3-selective inhibitors.

    Figure 29

    Figure 29. (A) Hydroxamate-based dual HDAC1/3 inhibitors. (B) Benzamide-based dual HDAC1/3 inhibitors. (C) Hydrazide-based dual HDAC1/3 inhibitors. (D) Romidepsin-based dual HDAC1/3 selective inhibitors. (E) Dual HDAC3/6 selective inhibitors.

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